Cyclohexyl acid isoxazole azines as LPA antagonists

ABSTRACT

The present invention provides compounds of Formula (Ia) or (Ib): (Ia) or (Ib), or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein all the variables are as defined herein. These compounds are selective LPA receptor inhibitors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 371 of International Application No. PCT/US2018/066111 filed on Dec. 18, 2018, which claims the priority benefit ofU.S. Provisional Application 62/607,398, filed Dec. 19, 2017; each ofwhich is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to novel substituted isoxazole compounds,compositions containing them, and methods of using them, for example,for the treatment of disorders associated with one or more of thelysophosphatidic acid (LPA) receptors.

BACKGROUND OF THE INVENTION

Lysophospholipids are membrane-derived bioactive lipid mediators, ofwhich one of the most medically important is lysophosphatidic acid(LPA). LPA is not a single molecular entity but a collection ofendogenous structural variants with fatty acids of varied lengths anddegrees of saturation (Fujiwara et al., J Biol. Chem., 2005, 280,35038-35050). The structural backbone of the LPAs is derived fromglycerol-based phospholipids such as phosphatidylcholine (PC) orphosphatidic acid (PA).

The LPAs are bioactive lipids (signaling lipids) that regulate variouscellular signaling pathways by binding to the same class of7-transmembrane domain G protein-coupled (GPCR) receptors (Chun, J.,Hla, T., Spiegel, S., Moolenaar, W., Editors, LysophospholipidReceptors: Signaling and Biochemistry, 2013, Wiley; ISBN:978-0-470-56905-4 & Zhao, Y. et al, Biochim. Biophys. Acta (BBA)-Mol.Cell Biol. Of Lipids, 2013, 1831, 86-92). The currently known LPAreceptors are designated as LPA₁, LPA₂, LPA₃, LPA₄, LPA₅ and LPA₆ (Choi,J. W., Annu. Rev. Pharmacol. Toxicol., 2010, 50, 157-186; Kihara, Y., etal, Br. J. Pharmacol., 2014, 171, 3575-3594).

The LPAs have long been known as precursors of phospholipid biosynthesisin both eukaryotic and prokaryotic cells, but the LPAs have emerged onlyrecently as signaling molecules that are rapidly produced and releasedby activated cells, notably platelets, to influence target cells byacting on specific cell-surface receptors (see, e.g., Moolenaar et al.,BioEssays, 2004, 26, 870-881, and van Leewen et al., Biochem. Soc.Trans., 2003, 31, 1209-1212). Besides being synthesized and processed tomore complex phospholipids in the endoplasmic reticulum, LPAs can begenerated through the hydrolysis of pre-existing phospholipids followingcell activation; for example, the sn-2 position is commonly missing afatty acid residue due to deacylation, leaving only the sn-1 hydroxylesterified to a fatty acid. Moreover, a key enzyme in the production ofLPA, autotaxin (lysoPLD/NPP2), may be the product of an oncogene, asmany tumor types up-regulate autotaxin (Brindley, D., J. Cell Biochem.2004, 92, 900-12). The concentrations of LPAs in human plasma & serum aswell as human bronchoalveolar lavage fluid (BALF) have been reported,including determinations made using sensitive and specific LC/MS &LC/MS/MS procedures (Baker et al. Anal. Biochem., 2001, 292, 287-295;Onorato et al., J. Lipid Res., 2014, 55, 1784-1796).

LPA influences a wide range of biological responses, ranging frominduction of cell proliferation, stimulation of cell migration andneurite retraction, gap junction closure, and even slime mold chemotaxis(Goetzl, et al., Scientific World J., 2002, 2, 324-338; Chun, J., Hla,T., Spiegel, S., Moolenaar, W., Editors, Lysophospholipid Receptors:Signaling and Biochemistry, 2013, Wiley; ISBN: 978-0-470-56905-4). Thebody of knowledge about the biology of LPA continues to grow as more andmore cellular systems are tested for LPA responsiveness. For instance,it is now known that, in addition to stimulating cell growth andproliferation, LPAs promote cellular tension and cell-surfacefibronectin binding, which are important events in wound repair andregeneration (Moolenaar et al., BioEssays, 2004, 26, 870-881). Recently,anti-apoptotic activity has also been ascribed to LPA, and it hasrecently been reported that PPARγ is a receptor/target for LPA (Simon etal., J. Biol. Chem., 2005, 280, 14656-14662).

Fibrosis is the result of an uncontrolled tissue healing process leadingto excessive accumulation and insufficient resorption of extracellularmatrix (ECM) which ultimately results in end-organ failure (Rockey, D.C., et al., New Engl. J. Med., 2015, 372, 1138-1149). The LPA₁ receptorhas been reported to be over-expressed in idiopathic pulmonary fibrosis(IPF) patients. LPA₁ receptor knockout mice were protected frombleomycin-induced lung fibrosis (Tager et al., Nature Med, 2008, 14,45-54). The LPA₁ antagonist BMS-986020 was shown to significantly reducethe rate of FVC (forced vital capacity) decline in a 26-week clinicaltrial in IPF patients (Palmer et al., Chest, 2018, 154, 1061-1069). LPApathway inhibitors (e.g. an LPA₁ antagonist) were shown to bechemopreventive anti-fibrotic agents in the treatment of hepatocellularcarcinoma in a rat model (Nakagawa et al., Cancer Cell, 2016, 30,879-890).

Thus, antagonizing the LPA₁ receptor may be useful for the treatment offibrosis such as pulmonary fibrosis, hepatic fibrosis, renal fibrosis,arterial fibrosis and systemic sclerosis, and thus the diseases thatresult from fibrosis (pulmonary fibrosis-Idiopathic Pulmonary Fibrosis[IPF], hepatic fibrosis-Non-alcoholic Steatohepatitis [NASH], renalfibrosis-diabetic nephropathy, systemic sclerosis-scleroderma, etc.).

SUMMARY OF THE INVENTION

The present invention provides novel substituted isoxazole compoundsincluding stereoisomers, tautomers, and pharmaceutically acceptablesalts or solvates thereof, which are useful as antagonists against oneor more of the lysophosphatidic acid (LPA) receptors, especially theLPA₁ receptor.

The present invention also provides processes and intermediates formaking the compounds of the present invention.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts or solvates thereof.

The compounds of the invention may be used in the treatment ofconditions in which LPA plays a role.

The compounds of the present invention may be used in therapy.

The compounds of the present invention may be used for the manufactureof a medicament for the treatment of a condition in which inhibition ofthe physiological activity of LPA is useful, such as diseases in whichan LPA receptor participates, is involved in the etiology or pathologyof the disease, or is otherwise associated with at least one symptom ofthe disease.

In another aspect, the present invention is directed to a method oftreating fibrosis of organs (liver, kidney, lung, heart and the like aswell as skin), liver diseases (acute hepatitis, chronic hepatitis, liverfibrosis, liver cirrhosis, portal hypertension, regenerative failure,non-alcoholic steatohepatitis (NASH), liver hypofunction, hepatic bloodflow disorder, and the like), cell proliferative disease [cancer (solidtumor, solid tumor metastasis, vascular fibroma, myeloma, multiplemyeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL)and the like) and invasive metastasis of cancer cell, and the like],inflammatory disease (psoriasis, nephropathy, pneumonia and the like),gastrointestinal tract disease (irritable bowel syndrome (IBS),inflammatory bowel disease (IBD), abnormal pancreatic secretion, and thelike), renal disease, urinary tract-associated disease (benign prostatichyperplasia or symptoms associated with neuropathic bladder disease,spinal cord tumor, hernia of intervertebral disk, spinal canal stenosis,symptoms derived from diabetes, lower urinary tract disease (obstructionof lower urinary tract, and the like), inflammatory disease of lowerurinary tract, dysuria, frequent urination, and the like), pancreasdisease, abnormal angiogenesis-associated disease (arterial obstructionand the like), scleroderma, brain-associated disease (cerebralinfarction, cerebral hemorrhage, and the like), neuropathic pain,peripheral neuropathy, and the like, ocular disease (age-related maculardegeneration (AMD), diabetic retinopathy, proliferativevitreoretinopathy (PVR), cicatricial pemphigoid, glaucoma filtrationsurgery scarring, and the like).

In another aspect, the present invention is directed to a method oftreating diseases, disorders, or conditions in which activation of atleast one LPA receptor by LPA contributes to the symptomology orprogression of the disease, disorder or condition. These diseases,disorders, or conditions may arise from one or more of a genetic,iatrogenic, immunological, infectious, metabolic, oncological, toxic,surgical, and/or traumatic etiology.

In another aspect, the present invention is directed to a method oftreating renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterialfibrosis and systemic sclerosis comprising administering to a patient inneed of such treatment a compound of the present invention as describedabove.

In one aspect, the present invention provides methods, compounds,pharmaceutical compositions, and medicaments described herein thatcomprise antagonists of LPA receptors, especially antagonists of LPA₁.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore, preferably one to two other agent(s).

These and other features of the invention will be set forth in expandedform as the disclosure continues.

DETAILED DESCRIPTION OF THE INVENTION I. Compounds of the Invention

In one aspect, the present invention provides, inter alia, compounds ofFormula (Ia) or (Ib):

or a stereoisomer, tautomer, or pharmaceutically acceptable salt orsolvate thereof, wherein

X¹, X², X³, and X⁴ are each independently CR⁶ or N; provided that nomore than two of X¹, X², X³, or X⁴ are N;

L is a covalent bond or C₁₋₄ alkylene substituted with 0 to 4 R⁷;

Z is NR⁸ or O;

the Y ring is phenyl or an azine moiety; and the term “azine” refers to6-membered heteroaryl wherein the ring members are selected from CH and1 to 4 nitrogen. In one embodiment, the azine moiety is a ring moietyselected from pyridine, diazine (e.g., pyrimidine, pyrazine, andpyridazine), triazine, and tetrazine;

R¹ is (—CH₂)_(a)R⁹;

a is an integer of 0 or 1;

R² is each independently halo, cyano, hydroxyl, amino, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₄₋₆ heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl,aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl, or haloalkoxy;

n is an integer of 0, 1, or 2; R³ is halo, cyano, hydroxyl, amino, oxo,—OR^(a), —SR^(a), ═S, —NR^(c)R^(c), ═NH, ═N—OH, ═NR^(a), ═N—OR^(a),—NO₂, —S(O)₂R^(a), —S(O)₂NHR^(b), —S(O)₂NR^(c)R^(c), —S(O)₂OR^(b),—OS(O)₂R^(b), —OS(O)₂OR^(b), —P(O)(OR^(b))(OR^(b)), —C(O)R^(b),—C(NR^(b))R^(b), —C(O)OR^(b), —C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c),—OC(O)R^(b), —NR^(b)C(O)R^(b), —OC(O)OR^(b), —NR^(b)C(O)OR^(b),—OC(O)NR^(c)R^(c), —NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(N—R^(b))R^(b),—NR^(b)(NR^(b))NR^(c)R^(c), (C₁₋₆ alkyl, C₁₋₆ deuterated alkyl (fullydeuterated or partially deuterated), C₁₋₆ heteroalkyl, 6- to 10-memberedaryl, arylalkyl, 5- to 10-membered heteroaryl, heteroarylalkyl, 3- to8-membered carbocyclyl, carbocyclylalkyl, 4- to 8-membered heterocyclyl,or heterocyclylalkyl; wherein the alkyl, heteroalkyl, aryl, heteroaryl,carbocyclyl, heterocyclyl, and R^(a), by themselves or as part ofanother group, are each independently substituted with 0 to 5 R^(d), andthe alkyl, by itself or as part of another group;

R^(a) is selected from C₁₋₆ alkyl, C₁₋₆ deuterated alkyl (fullydeuterated or partially deuterated), haloalkyl, hydroxyalkyl,aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, andheterocyclylalkyl;

R^(b) is each independently hydrogen or R^(a);

R^(c) is each independently R^(b); or alternatively, two R^(c), takentogether with the nitrogen atom to which they are attached, form a 4- to7-membered heterocyclyl;

R^(d) is each independently selected from R^(a), alkoxy, haloalkoxy,alkylamino, cycloalkylamino, heterocyclylamino, haloalkyl, hydroxyalkyl,aminoalkyl, cycloalkoxy, heterocyclyloxy, haloalkoxy, alkoxyalkoxy,haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino, arylamino,aralkylamino, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy,alkylthio, halo, cyano, hydroxyl, amino, oxo, —OR^(a), —SR^(a), ═S,-NR^(a)c, ═NH, ═N—OH, ═NR^(a), ═N—OR^(a), —NO₂, —S(O)₂R^(a),—S(O)₂NHR^(b), —S(O)₂NR^(c)R^(c), —S(O)₂OR^(b), —OS(O)₂R^(b),—OS(O)₂OR^(b), —P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(NR^(b))R^(b),—C(O)OR^(b), —C(O)NR^(c)R^(c), —C(NR^(b))NR^(a)C, —OC(O)R^(b),—NR^(b)C(O)R^(b), —OC(O)OR^(b), —NR^(b)C(O)OR^(b),—NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b), and—NR^(b)C(NR^(b))NR^(c)R^(c); or alternatively one or two R^(d) on alkyl,heteroalkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, takentogether with the atoms to which the R^(d) is attached, form a cyclic orbridge moiety;

R⁴ is each independently halo, cyano, hydroxyl, amino, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₄₋₆ heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl,aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl, or haloalkoxy; or R³and R⁴, taken together with the atoms to which they are attached, form amonocyclic or bicyclic ring moiety;

m is an integer of 0, 1, or 2;

R⁵ and R⁶ are each independently hydrogen, halo, cyano, hydroxyl, amino,C₁₋₆ alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl,alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;

R⁷ is halo, oxo, cyano, hydroxyl, amino, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₄₋₆ heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl,alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;

R⁸ is hydrogen or C₁₋₄ alkyl;

R⁹ is selected from —CN, —C(O)OR¹⁰, —C(O)NR^(11a)R^(11b),

R^(e) is C₁₋₆ alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,or haloalkoxyalkyl;

R¹⁰ is hydrogen or C₁₋₁₀ alkyl; and

R^(11a) and R^(11b) are each independently hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₄₋₆ heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl,aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy.

In one embodiment of Formula (Ia) or (Ib), X¹ is CR⁶, where R⁶ ishydrogen or C₁₋₄ alkyl (e.g., methyl).

In any one of the preceding embodiments of Formula (Ia) or (Ib), R⁶ ishydrogen or C₁₋₆ alkyl.

In any one of the preceding embodiments of Formula (Ia) or (Ib), L is acovalent bond or methylene.

In any one of the preceding embodiments of Formula (Ia) or (Ib),

the

moiety is

and

Y¹, Y², Y³, and Y⁴ are each independently N or CH with the proviso thatat least one of Y¹, Y², Y³, and Y⁴ is CH. In one embodiment, two of V,Y², Y³, and Y⁴ are CH. In another embodiment, three of Y¹, Y², Y³, andY⁴ are CH. In another embodiment, Y¹, Y², Y³, and Y⁴ are all CH.

In any one of the preceding embodiments of Formula (Ia) or (Ib),

R³ is halo, cyano, hydroxyl, amino, —OR^(a), —SR^(a), —NR^(c)R^(c), C₁₋₆alkyl, C₁₋₆ heteroalkyl, 6- to 10-membered aryl, arylalkyl, 5- to10-membered heteroaryl, heteroarylalkyl, 3- to 8-membered carbocyclyl,carbocyclylalkyl, 4- to 8-membered heterocyclyl, or heterocyclylalkyl;wherein the alkyl, heteroalkyl, aryl, heteroaryl, carbocyclyl,heterocyclyl, and R^(a), by themselves or as part of another group, areeach independently substituted with 0 to 5 R^(d),

R^(a) is selected from C₁₋₆ alkyl, haloalkyl, hydroxyalkyl, aminoalkyl,alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, andheterocyclylalkyl;

R^(b) is each independently hydrogen or R^(a);

R^(c) is each independently R^(b); or alternatively, two R^(c), takentogether with the nitrogen atom to which they are attached, form a 4- to7-membered heterocyclyl;

R^(d) is each independently selected from R^(a), alkoxy, haloalkoxy,alkylamino, cycloalkylamino, heterocyclylamino, haloalkyl, hydroxyalkyl,aminoalkyl, cycloalkoxy, heterocyclyloxy, haloalkoxy, alkoxyalkoxy,haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino, arylamino,aralkylamino, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy,alkylthio, halo, cyano, hydroxyl, amino, oxo, —OR^(a), —SR^(a), and—NR^(c)R^(c); or alternatively one or two R^(d) on alkyl, heteroalkyl,aryl, heteroaryl, carbocyclyl, or heterocyclyl, taken together with theatoms to which the R^(d) is attached, form a cyclic or bridge moiety.

In any one of the preceding embodiments of Formula (Ia) or (Ib), thecompound is represented by Formula (IIa) or Formula (IIb):

Y¹, Y², Y³, and Y⁴ are each independently N or CH;

R^(7a) is hydrogen, halo, oxo, cyano, hydroxyl, amino, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₄₋₆ heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl,aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;

f is an integer of 0, 1, or 2;

n is 0 or 1;

R⁵ is hydrogen or C₁₋₄ alkyl; and

R¹, R², R³, R⁴, m, X¹, X², X³, X⁴, and Z are the same as defined above.

In one embodiment of Formula (IIa) or (III)), X¹ is CR⁶, where R⁶ ishydrogen or C₁₋₄ alkyl.

In any one of the preceding embodiments of Formula (IIa) or (III)), X³is N.

In any one of the preceding embodiments of Formula (IIa) or (IIb),

the moiety is selected from

R^(6a) is each independently halo, cyano, hydroxyl, amino, C₁₋₆ alkyl,alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,haloalkoxyalkyl, alkoxy, or haloalkoxy; and

d is an integer of 0, 1, or 2.

In any one of the preceding embodiments of Formula (IIa) or (IIb), L isa covalent bond or methylene, or f is 0 or 1. In one embodiment, R^(7a)is hydrogen.

In any one of the preceding embodiments of Formula (IIa) or (IIb), R⁸ ishydrogen or methyl.

In any one of the preceding embodiments of Formula (IIa) or (IIb), R¹ isCO₂H. In one embodiment, R² is hydrogen.

In any one of the preceding embodiments of Formula (IIa) or (IIb), thecompound is represented by Formula (IIIc) or (IIIb):

Y¹, Y², and Y³ are each independently N or CH;

R^(2a) is hydrogen, chloro, fluoro, or C₁₋₄ alkyl;

L is a covalent bond or CH₂;

Z is O or NH; and

R¹, R³, R⁴, m, X¹, X², X³, and X⁴ are the same as defined above.

In one embodiment of Formula (IIIa) or (IIIb), one of Y¹, Y², and Y³ isCH. In another embodiment of Formula (IIIa) or (IIIb), two of Y¹, Y²,and Y³ are CH. In another embodiment of Formula (IIIa) or (IIIb), Y¹,Y², and Y³ are all CH.

In any one of the preceding embodiments of Formula (IIIa) or (IIIb), the

moiety is selected from

In one embodiment, R^(2a) is hydrogen.

In any one of the preceding embodiments of Formula (IIIa) or (IIIb), R¹is CO₂H.

In any one of the preceding embodiments of Formula (Ma) or (IIIb), X¹ isCR⁶; X² is N or CH; X³ is N; X⁴ is N or CH; and R⁶ is hydrogen, halo,cyano, C₁₋₆ alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, oralkoxy. In one embodiment, X⁴ is CH.

In any one of the preceding embodiments of Formula (IIIa) or (IIIb),

the

moiety is selected from

In any one of the preceding embodiments of Formula (IIIa) or (IIIb),

the

moiety is selected from

In any one of the preceding embodiments of Formula (IIIa) or (IIIb),

the

moiety is

and

m is 0 or 1.

In one embodiment, R⁴ is C₁₋₄ alkyl, C₁₋₄ alkoxy, or halo.

In any one of the preceding embodiments of Formula (IIIa) or (IIIb),

the

moiety is

and m is 0 or 1.

In any one of the preceding embodiments of Formula (IIIa) or (IIIb),

R³ is halo, cyano, hydroxyl, amino, —OR^(a), —SR^(a), —NR^(c)R^(c), C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ heteroalkyl, 6- to 10-membered aryl,arylalkyl, 5- to 10-membered heteroaryl, heteroarylalkyl, 3- to8-membered carbocyclyl, carbocyclylalkyl, 4- to 8-membered heterocyclyl,or heterocyclylalkyl; wherein the alkyl, heteroalkyl, aryl, heteroaryl,carbocyclyl, heterocyclyl, and R^(a), by themselves or as part ofanother group, are each independently substituted with 0 to 5 R^(d);

R^(a) is selected from C₁₋₆ alkyl, haloalkyl, hydroxyalkyl, aminoalkyl,alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, andheterocyclylalkyl;

R^(b) is each independently hydrogen or R^(a);

R^(c) is each independently R^(b); or alternatively, two R^(c), takentogether with the nitrogen atom to which they are attached, form a 4- to7-membered heterocyclyl;

R^(d) is each independently selected from R^(a), alkoxy, haloalkoxy,alkylamino, cycloalkylamino, heterocyclylamino, haloalkyl, hydroxyalkyl,aminoalkyl, cycloalkoxy, heterocyclyloxy, haloalkoxy, alkoxyalkoxy,haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino, arylamino,aralkylamino, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy,alkylthio, halo, cyano, hydroxyl, amino, oxo, —OR^(a), —SR^(a), and—NR^(c)R^(c); or alternatively one or two R^(d) on alkyl, heteroalkyl,aryl, heteroaryl, carbocyclyl, or heterocyclyl, taken together with theatoms to which the R^(d) is attached, form a cyclic or bridge moiety.

m is 0, 1, or 2; and

R⁴ is each independently halo, cyano, hydroxyl, amino, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₄₋₆ heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl,aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl, or haloalkoxy.

In any one of the preceding embodiments of Formula (IIIa) or (IIIb), R³is C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆cycloalkyl, phenyl, benzyl, (a 6-membered heteroaryl containing 1 to 3heteroatoms each of which is independently selected from N, O, and S),alkoxy, —O-cycloalkyl, —O-phenyl, —O-benzyl, and —NH-alkyl; and each ofthe alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, phenyl, benzyl,and heteroaryl, by itself or as part of another group, is independentlysubstituted with 0 to 3 R^(d); and R^(d) is halo, cyano, hydroxyl,amino, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, or alkoxy.

In one embodiment of the present invention, the compound is selectedfrom any one of the Examples as described in the specification, or astereoisomer, a tautomer, or a pharmaceutically acceptable salt orsolvate thereof.

In another embodiment of the present invention, the compound is selectedfrom Examples 1 to 30 as described in the specification, or astereoisomer, a tautomer, or a pharmaceutically acceptable salt orsolvate thereof.

In another embodiment of the present invention, the compound is selectedfrom Examples 1 to 15 as described in the specification, or astereoisomer, a tautomer, or a pharmaceutically acceptable salt orsolvate thereof.

In one embodiment, the compounds of the present invention have hLPA₁IC₅₀ values≤5000 nM, using the LPA₁ functional antagonist assay; inanother embodiment, the compounds of the present invention have hLPA₁IC₅₀ values S≤1000 nM; in another embodiment, the compounds of thepresent invention have hLPA₁ IC₅₀ values≤500 nM; in another embodiment,the compounds of the present invention have hLPA₁ IC₅₀ values≤200 nM; inanother embodiment, the compounds of the present invention have hLPA₁IC₅₀ values≤100 nM; in another embodiment, the compounds of the presentinvention have hLPA₁ IC₅₀ values≤50 nM.

II. Other Embodiments of the Invention

In some embodiments, the compound of Formula (Ia) or (Ib), or apharmaceutically acceptable salt or solvate thereof, is an antagonist ofat least one LPA receptor. In some embodiments, the compound of Formula(Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof,is an antagonist of LPA₁. In some embodiments, the compound of Formula(Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof,is an antagonist of LPA₂. In some embodiments, the compound of Formula(Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof,is an antagonist of LPA₃.

In some embodiments, presented herein are compounds selected from activemetabolites, tautomers, pharmaceutically acceptable salts or solvates ofa compound of Formula (Ia) or (Ib).

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s).

In another embodiment, the present invention provides a method for thetreatment of a condition associated with LPA receptor mediated fibrosis,comprising administering to a patient in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof. As used herein, the term“patient” encompasses all mammalian species.

In another embodiment, the present invention provides a method oftreating a disease, disorder, or condition associated with dysregulationof lysophosphatidic acid receptor 1 (LPA₁) in a patient in need thereof,comprising administering a therapeutically effective amount of acompound of the present invention, or a stereoisomer, a tautomer, or apharmaceutically acceptable salt or solvate thereof, to the patient. Inone embodiment of the method, the disease, disorder, or condition isrelated to pathological fibrosis, transplant rejection, cancer,osteoporosis, or inflammatory disorders. In one embodiment of themethod, the pathological fibrosis is pulmonary, liver, renal, cardiac,dernal, ocular, or pancreatic fibrosis. In one embodiment of the method,the disease, disorder, or condition is idiopathic pulmonary fibrosis(IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liverdisease (NAFLD), chronic kidney disease, diabetic kidney disease, andsystemic sclerosis. In one embodiment of the method, the cancer is ofthe bladder, blood, bone, brain, breast, central nervous system, cervix,colon, endometrium, esophagus, gall bladder, genitalia, genitourinarytract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral ornasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine,large intestine, stomach, testicle, or thyroid.

In another embodiment, the present invention provides a method oftreating fibrosis in a mammal comprising administering a therapeuticallyeffective amount of a compound of the present invention, or astereoisomer, a tautomer, or a pharmaceutically acceptable salt orsolvate thereof, to the mammal in need thereof. In one embodiment of themethod, the fibrosis is idiopathic pulmonary fibrosis (IPF),nonalcoholic steatohepatitis (NASH), chronic kidney disease, diabetickidney disease, and systemic sclerosis.

In another embodiment, the present invention provides a method oftreating lung fibrosis (idiopathic pulmonary fibrosis), asthma, chronicobstructive pulmonary disease (COPD), renal fibrosis, acute kidneyinjury, chronic kidney disease, liver fibrosis (non-alcoholicsteatohepatitis), skin fibrosis, fibrosis of the gut, breast cancer,pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bonecancer, colon cancer, bowel cancer, head and neck cancer, melanoma,multiple myeloma, chronic lymphocytic leukemia, cancer pain, tumormetastasis, transplant organ rejection, scleroderma, ocular fibrosis,age related macular degeneration (AMD), diabetic retinopathy, collagenvascular disease, atherosclerosis, Raynaud's phenomenon, or neuropathicpain in a mammal comprising administering a therapeutically effectiveamount of a compound of the present invention, or a stereoisomer, atautomer, or a pharmaceutically acceptable salt or solvate thereof, tothe mammal in need thereof.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting it development; and/or (b)relieving the disease-state, i.e., causing regression of the diseasestate. As used herein, “treating” or “treatment” also include theprotective treatment of a disease state to reduce and/or minimize therisk and/or reduction in the risk of recurrence of a disease state byadministering to a patient a therapeutically effective amount of atleast one of the compounds of the present invention or a or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof. Patients may be selected for such protective therapybased on factors that are known to increase risk of suffering a clinicaldisease state compared to the general population. For protectivetreatment, conditions of the clinical disease state may or may not bepresented yet. The protective treatment can be divided into (a) primaryprophylaxis and (b) secondary prophylaxis. Primary prophylaxis isdefined as treatment to reduce or minimize the risk of a disease statein a patient that has not yet presented with a clinical disease state,whereas secondary prophylaxis is defined as minimizing or reducing therisk of a recurrence or second occurrence of the same or similarclinical disease state.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsoto be understood that each individual element of the embodiments is itsown independent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

III. Chemistry

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans- (or E- and Z—) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention.

The term “stereoisomer” refers to isomers of identical constitution thatdiffer in the arrangement of their atoms in space. Enantiomers anddiastereomers are examples of stereoisomers. The term “enantiomer”refers to one of a pair of molecular species that are mirror images ofeach other and are not superimposable. The term “diastereomer” refers tostereoisomers that are not mirror images. The term “racemate” or“racemic mixture” refers to a composition composed of equimolarquantities of two enantiomeric species, wherein the composition isdevoid of optical activity.

The symbols “R” and “S” represent the configuration of substituentsaround a chiral carbon atom(s). The isomeric descriptors “R” and “S” areused as described herein for indicating atom configuration(s) relativeto a core molecule and are intended to be used as defined in theliterature (IUPAC Recommendations 1996, Pure and Applied Chemistry,68:2193-2222 (1996)).

The term “chiral” refers to the structural characteristic of a moleculethat makes it impossible to superimpose it on its mirror image. The term“homochiral” refers to a state of enantiomeric purity. The term “opticalactivity” refers to the degree to which a homochiral molecule ornonracemic mixture of chiral molecules rotates a plane of polarizedlight.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. While “alkyl” denotes amonovalent saturated aliphatic radical (such as ethyl), “alkylene”denotes a bivalent saturated aliphatic radical (such as ethylene). Forexample, “C₁ to C₁₀ alkyl” or “C₁₋₁₀ alkyl” is intended to include C₁,C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. “C₁ to C₁₀alkylene” or “C₁₋₁₀ alkylene”, is intended to include C₁, C₂, C₃, C₄,C₅, C₆, C₇, C₈, C₉, and C₁₀ alkylene groups. Additionally, for example,“C₁ to C₆ alkyl” or “C₁₋₆ alkyl” denotes alkyl having 1 to 6 carbonatoms; and “C₁ to C₆ alkylene” or “C₁₋₆ alkylene” denotes alkylenehaving 1 to 6 carbon atoms; and “C₁ to C₄ alkyl” or “C₁₋₄ alkyl” denotesalkyl having 1 to 4 carbon atoms; and “C₁ to C₄ alkylene” or “C₁₋₄alkylene” denotes alkylene having 1 to 4 carbon atoms. Alkyl group canbe unsubstituted or substituted with at least one hydrogen beingreplaced by another chemical group. Example alkyl groups include, butare not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e. g., n-butyl, isobutyl, t-butyl), and pentyl (e.g.,n-pentyl, isopentyl, neopentyl). When “C₀ alkyl” or “C₀ alkylene” isused, it is intended to denote a direct bond. Furthermore, the term“alkyl”, by itself or as part of another group, such as alkylamino,haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl,haloalkoxyalkyl, and haloalkoxy, can be an alkyl having 1 to 4 carbonatoms, or 1 to 6 carbon atoms, or 1 to 10 carbon atoms.

“Heteroalkyl” refers to an alkyl group where one or more carbon atomshave been replaced with a heteroatom, such as, O, N, or S. For example,if the carbon atom of the alkyl group which is attached to the parentmolecule is replaced with a heteroatom (e.g., O, N, or S) the resultingheteroalkyl groups are, respectively, an alkoxy group (e.g., —OCH₃,etc.), an alkylamino (e.g., —NHCH₃, —N(CH₃)₂, etc.), or a thioalkylgroup (e.g., —SCH₃). If a non-terminal carbon atom of the alkyl groupwhich is not attached to the parent molecule is replaced with aheteroatom (e.g., O, N, or S) and the resulting heteroalkyl groups are,respectively, an alkyl ether (e.g., —CH₂CH₂—O—CH₃, etc.), analkylaminoalkyl (e.g., —CH₂NHCH₃, —CH₂N(CH₃)₂, etc.), or a thioalkylether (e.g., —CH₂—S—CH₃). If a terminal carbon atom of the alkyl groupis replaced with a heteroatom (e.g., O, N, or S), the resultingheteroalkyl groups are, respectively, a hydroxyalkyl group (e.g.,—CH₂CH₂—OH), an aminoalkyl group (e.g., —CH₂NH₂), or an alkyl thiolgroup (e.g., —CH₂CH₂—SH). A heteroalkyl group can have, for example, 1to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. AC₁-C₆ heteroalkyl group means a heteroalkyl group having 1 to 6 carbonatoms.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having the specified number ofcarbon atoms and one or more, preferably one to two, carbon-carbondouble bonds that may occur in any stable point along the chain. Forexample, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl” (or alkenylene), isintended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. Examples ofalkenyl include, but are not limited to, ethenyl, 1-propenyl,2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and4-methyl-3-pentenyl.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon triple bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkynyl” or “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

As used herein, “arylalkyl” (a.k.a. aralkyl), “heteroarylalkyl”“carbocyclylalkyl” or “heterocyclylalkyl” refers to an acyclic alkylradical in which one of the hydrogen atoms bonded to a carbon atom,typically a terminal or sp³ carbon atom, is replaced with an aryl,heteroaryl, carbocyclyl, or heterocyclyl radical, respectively. Typicalarylalkyl groups include, but are not limited to, benzyl,2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. The arylalkyl, heteroarylalkyl,carbocyclylalkyl, or heterocyclylalkyl group can comprise 4 to 20 carbonatoms and 0 to 5 heteroatoms, e.g., the alkyl moiety may contain 1 to 6carbon atoms.

The term “benzyl”, as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group, wherein said phenylgroup may optionally be substituted with 1 to 5 groups, preferably 1 to3 groups, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃,OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, andCO₂CH₃. “Benzyl” can also be represented by formula “Bn”.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. “C₁ to C₆alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intended to include C₁, C₂,C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxy groups include, but arenot limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), and t-butoxy. Similarly, “alkylthio” or “thioalkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through a sulphur bridge; for example, methyl-S—and ethyl-S—.

The term “alkanoyl” or “alkylcarbonyl” as used herein alone or as partof another group refers to alkyl linked to a carbonyl group. Forexample, alkylcarbonyl may be represented by alkyl-C(O)—. “C₁ to C₆alkylcarbonyl” (or alkylcarbonyl), is intended to include C₁, C₂, C₃,C₄, C₅, and C₆ alkyl-C(O)— groups.

The term “alkylsulfonyl” or “sulfonamide” as used herein alone or aspart of another group refers to alkyl or amino linked to a sulfonylgroup. For example, alkylsulfonyl may be represented by —S(O)₂R′, whilesulfonamide may be represented by —S(O)₂NR^(c)R^(d). R′ is C₁ to C₆alkyl; and R^(c) and R^(d) are the same as defined below for “amino”

The term “carbamate” as used herein alone or as part of another grouprefers to oxygen linked to an amido group. For example, carbamate may berepresented by N(R^(c)R^(d))—C(O)—O—, and R^(c) and R^(d) are the sameas defined below for “amino”

The term “amido” as used herein alone or as part of another group refersto amino linked to a carbonyl group. For example, amido may berepresented by N(R^(c)R^(d))—C(O)—, and R^(c) and R^(d) are the same asdefined below for “amino”.

The term “amino” is defined as —NR^(c1)R^(c2) wherein R^(c1) and R^(c2)are independently H or C₁₋₆ alkyl; or alternatively, R^(c1) and R^(c2),taken together with the atoms to which they are attached, form a 3- to8-membered heterocyclic ring which is optionally substituted with one ormore group selected from halo, cyano, hydroxyl, amino, oxo, C₁₋₆ alkyl,alkoxy, and aminoalkyl. When R^(c1) or R^(c2) (or both of them) is C₁₋₆alkyl, the amino group can also be referred to as alkylamino Examples ofalkylamino group include, without limitation, methylamino, ethylamino,propylamino, isopropylamino and the like. In one embodiment, amino is—NH₂.

The term “aminoalkyl” refers to an alkyl group on which one of thehydrogen atoms is replaced by an amino group. For example, aminoalkylmay be represented by N(R^(c1)R^(c2))-alkylene-. “C₁ to C₆” or “C₁₋₆”aminoalkyl” (or aminoalkyl), is intended to include C₁, C₂, C₃, C₄, C₅,and C₆ aminoalkyl groups.

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chlorine, bromine, fluorine, and iodine, with chlorineor fluorine being preferred.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with one or more halogens. “C₁ to C₆haloalkyl” or “C₁₋₆ haloalkyl” (or haloalkyl), is intended to includeC₁, C₂, C₃, C₄, C₅, and C₆ haloalkyl groups. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” that is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morefluorine atoms. The term “polyhaloalkyl” as used herein refers to an“alkyl” group as defined above which includes from 2 to 9, preferablyfrom 2 to 5, halo substituents, such as F or Cl, preferably F, such aspolyfluoroalkyl, for example, CF₃CH₂, CF₃ or CF₃CF₂CH₂.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁ to C₆ haloalkoxy” or “C₁₋₆ haloalkoxy”,is intended to include C₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups.Examples of haloalkoxy include, but are not limited to,trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy.Similarly, “haloalkylthio” or “thiohaloalkoxy” represents a haloalkylgroup as defined above with the indicated number of carbon atomsattached through a sulphur bridge; for example trifluoromethyl-S—, andpentafluoroethyl-S—. The term “polyhaloalkyloxy” as used herein refersto an “alkoxy” or “alkyloxy” group as defined above which includes from2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl,preferably F, such as polyfluoroalkoxy, for example, CF₃CH₂O, CF₃O orCF₃CF₂CH₂O.

“Hydroxyalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more hydroxyl (OH). “C₁ to C₆hydroxyalkyl” (or hydroxyalkyl), is intended to include C₁, C₂, C₃, C₄,C₅, and C₆ hydroxyalkyl groups.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. “C₃ to C₈ cycloalkyl” or “C₃₋₈cycloalkyl” is intended to include C₃, C₄, C₅, C₆, C₇, and C₈ cycloalkylgroups, including monocyclic, bicyclic, and polycyclic rings. Examplecycloalkyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkylgroups such as 1-methylcyclopropyl and 2-methylcyclopropyl and spiro andbridged cycloalkyl groups are included in the definition of“cycloalkyl”.

The term “cycloheteroalkyl” refers to cyclized heteroalkyl groups,including mono-, bi- or poly-cyclic ring systems. “C₃ to C₇cycloheteroalkyl” or “C₃₋₇ cycloheteroalkyl” is intended to include C₃,C₄, C₅, C₆, and C₇ cycloheteroalkyl groups. Example cycloheteroalkylgroups include, but are not limited to, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,and piperazinyl. Branched cycloheteroalkyl groups, such aspiperidinylmethyl, piperazinylmethyl, morpholinylmethyl,pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, and pyrazinylmethyl,are included in the definition of “cycloheteroalkyl”.

As used herein, “carbocycle”, “carbocyclyl” or “carbocyclic residue” isintended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclicor bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic ortricyclic hydrocarbon ring, any of which may be saturated, partiallyunsaturated, unsaturated or aromatic. Examples of such carbocyclesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl,cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shownabove, bridged rings are also included in the definition of carbocycle(e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,and indanyl. When the term “carbocyclyl” is used, it is intended toinclude “aryl”. A bridged ring occurs when one or more carbon atoms linktwo non-adjacent carbon atoms. Preferred bridges are one or two carbonatoms. It is noted that a bridge always converts a monocyclic ring intoa tricyclic ring. When a ring is bridged, the substituents recited forthe ring may also be present on the bridge.

Furthermore, the term “carbocyclyl”, including “cycloalkyl” and“cycloalkenyl”, as employed herein alone or as part of another groupincludes saturated or partially unsaturated (containing 1 or 2 doublebonds) cyclic hydrocarbon groups containing 1 to 3 rings, includingmonocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of3 to 20 carbons forming the rings, preferably 3 to 10 carbons or 3 to 6carbons, forming the ring and which may be fused to 1 or 2 aromaticrings as described for aryl, which include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl andcyclododecyl, cyclohexenyl,

any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, nitro, cyano, thiol and/or alkylthio and/or any ofthe alkyl substituents.

As used herein, the term “bicyclic carbocyclyl” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which issaturated, partially unsaturated, or unsaturated. The bicycliccarbocyclic group may be attached to its pendant group at any carbonatom which results in a stable structure. The bicyclic carbocyclic groupdescribed herein may be substituted on any carbon if the resultingcompound is stable. Examples of a bicyclic carbocyclic group are, butnot limited to, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and indanyl.

As used herein, the term “aryl”, as employed herein alone or as part ofanother group, refers to monocyclic or polycyclic (including bicyclicand tricyclic) aromatic hydrocarbons, including, for example, phenyl,naphthyl, anthracenyl, and phenanthranyl. Aryl moieties are well knownand described, for example, in Lewis, R. J., ed., Hawley's CondensedChemical Dictionary, 13th Edition, John Wiley & Sons, Inc., New York(1997). In one embodiment, the term “aryl” denotes monocyclic andbicyclic aromatic groups containing 6 to 10 carbons in the ring portion(such as phenyl or naphthyl including 1-naphthyl and 2-naphthyl). Forexample, “C₆ or C₁₀ aryl” or “C₆₋₁₀ aryl” refers to phenyl and naphthyl.Unless otherwise specified, “aryl”, “C₆ or C₁₀ aryl”, “C₆₋₁₀ aryl”, or“aromatic residue” may be unsubstituted or substituted with 1 to 5groups, preferably 1 to 3 groups, selected from —OH, —OCH₃, —Cl, —F,—Br, —I, —CN, —NO₂, —NH₂, —N(CH₃)H, —N(CH₃)₂, —CF₃, —OCF₃, —C(O)CH₃,—SCH₃, —S(O)CH₃, —S(O)₂CH₃, —CH₃, —CH₂CH₃, —CO₂H, and —CO₂CH₃.

The term “benzyl”, as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group, wherein said phenylgroup may optionally be substituted with 1 to 5 groups, preferably 1 to3 groups, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃,OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, andCO₂CH₃.

As used herein, the term “heterocycle”, “heterocyclyl”, or “heterocyclicgroup” is intended to mean a stable 3-, 4-, 5-, 6-, or 7-memberedmonocyclic or 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-memberedpolycyclic (including bicyclic and tricyclic) heterocyclic ring that issaturated, or partially unsaturated, and that contains carbon atoms and1, 2, 3 or 4 heteroatoms independently selected from N, O and S; andincluding any polycyclic group in which any of the above-definedheterocyclic rings is fused to a carbocyclic or an aryl (e.g., benzene)ring. That is, the term “heterocycle”, “heterocyclyl”, or “heterocyclicgroup” includes non-aromatic ring systems, such as heterocycloalkyl andheterocycloalkenyl. The nitrogen and sulfur heteroatoms may optionallybe oxidized (i.e., N→O and S(O)_(p), wherein p is 0, 1 or 2). Thenitrogen atom may be substituted or unsubstituted (i. e., N or NRwherein R is H or another substituent, if defined). The heterocyclicring may be attached to its pendant group at any heteroatom or carbonatom that results in a stable structure. The heterocyclic ringsdescribed herein may be substituted on carbon or on a nitrogen atom ifthe resulting compound is stable. A nitrogen in the heterocycle mayoptionally be quaternized. It is preferred that when the total number ofS and O atoms in the heterocycle exceeds 1, then these heteroatoms arenot adjacent to one another. It is preferred that the total number of Sand O atoms in the heterocycle is not more than 1. Examples ofhetercyclyl include, without limitation, azetidinyl, piperazinyl,piperidinyl, piperidonyl, piperonyl, pyranyl, morpholinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,morpholinyl, dihydrofuro[2,3-b]tetrahydrofuran.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromN, O and S. Of the two fused rings, one ring is a 5- or 6-memberedmonocyclic aromatic ring comprising a 5-membered heteroaryl ring, a6-membered heteroaryl ring or a benzo ring, each fused to a second ring.The second ring is a 5- or 6-membered monocyclic ring which issaturated, partially unsaturated, or unsaturated, and comprises a5-membered heterocycle, a 6-membered heterocycle or a carbocycle(provided the first ring is not benzo when the second ring is acarbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1. Examples of a bicyclic heterocyclic group are, but notlimited to, 1,2,3,4-tetrahydroquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl,2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl,and 1,2,3,4-tetrahydro-quinazolinyl.

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more atoms (i.e., C, O, N, or S) linktwo non-adjacent carbon or nitrogen atoms. Examples of bridged ringsinclude, but are not limited to, one carbon atom, two carbon atoms, onenitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It isnoted that a bridge always converts a monocyclic ring into a tricyclicring. When a ring is bridged, the substituents recited for the ring mayalso be present on the bridge.

As used herein, the term “heteroaryl” is intended to mean stablemonocyclic and polycyclic (including bicyclic and tricyclic) aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted orunsubstituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2).

Examples of heteroaryl also include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,1H-indazolyl, imidazolopyridinyl, indolenyl, indolinyl, indolizinyl,indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl,oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl,phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathianyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl,pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl,pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl.

Examples of 5- to 10-membered heteroaryl include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrazolyl, imidazolyl, imidazolidinyl,indolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl,thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl,benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiofuranyl,benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl,benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl,isoquinolinyl, octahydroisoquinolinyl, isoxazolopyridinyl, quinazolinyl,quinolinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl,imidazolopyridinyl, and pyrazolopyridinyl. Examples of 5- to 6-memberedheteroaryl include, but are not limited to, pyridinyl, furanyl, thienyl,pyrrolyl, pyrazolyl, pyrazinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl,thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl. In someembodiments, the heteroaryl are selected from benzthiazolyl,imidazolpyridinyl, pyrrolopyridinyl, quinolinyl, and indolyl.

Unless otherwise indicated, “carbocyclyl” or “heterocyclyl” includes oneto three additional rings fused to the carbocyclic ring or theheterocyclic ring (such as aryl, cycloalkyl, heteroaryl orcycloheteroalkyl rings), for example,

and may be optionally substituted through available carbon or nitrogenatoms (as applicable) with 1, 2, or 3 groups selected from hydrogen,halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl,trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl-alkyl,cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl,aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl,arylalkenyl, aminocarbonylaryl, arylthio, arylsulfinyl, arylazo,heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy,hydroxy, nitro, cyano, thiol, alkylthio, arylthio, heteroarylthio,arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl,alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl,a&ylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino,arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino andarylsulfonaminocarbonyl and/or any of the alkyl substituents set outherein.

When any of the terms alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl are used as part of another group,the number of carbon atoms and ring members are the same as thosedefined in the terms by themselves. For example, alkoxy, haloalkoxy,alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy,alkoxyalkoxy, haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino,alkylthio, and the like each independently contains the number of carbonatoms which are the same as defined for the term “alkyl”, such as 1 to 4carbon atoms, 1 to 6 carbon atoms, 1 to 10 carbon atoms, etc. Similarly,cycloalkoxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino,aralkylamino, arylamino, aryloxy, aralkyloxy, heteroaryloxy,heteroarylalkyloxy, and the like each independently contains ringmembers which are the same as defined for the terms “cycloalkyl”,“heterocyclyl”, “aryl”, and “heteroaryl”, such as 3 to 6-membered, 4 to7-membered, 6 to 10-membered, 5 to 10-membered, 5 or 6-membered, etc.

In accordance with a convention used in the art, a bond pointing to abold line, such as

used in structural formulas herein, depicts the bond that is the pointof attachment of the moiety or substituent to the core or backbonestructure.

In accordance with a convention used in the art, a wavy or squiggly bondin a structural formula, such as

is used to depict a stereogenic center of the carbon atom to which X′,Y′, and Z′ are attached and is intended to represent both enantiomers ina single FIGURE. That is, a structural formula with such as wavy bonddenotes each of the enantiomers individually, such as

as well as a racemic mixture thereof. When a wavy or squiggly bond isattached to a double bond (such as C═C or C═N) moiety, it include cis-or trans- (or E- and Z—) geometric isomers or a mixture thereof.

It is understood herein that if a carbocyclic or heterocyclic moiety maybe bonded or otherwise attached to a designated substrate throughdiffering ring atoms without denoting a specific point of attachment,then all possible points are intended, whether through a carbon atom or,for example, a trivalent nitrogen atom. For example, the term “pyridyl”means 2-, 3- or 4-pyridyl, the team “thienyl” means 2- or 3-thienyl, andso forth.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

One skilled in the art will recognize that substituents and othermoieties of the compounds of the present invention should be selected inorder to provide a compound which is sufficiently stable to provide apharmaceutically useful compound which can be formulated into anacceptably stable pharmaceutical composition. Compounds of the presentinvention which have such stability are contemplated as falling withinthe scope of the present invention.

The term “counter ion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate. The term“metal ion” refers to alkali metal ions such as sodium, potassium orlithium and alkaline earth metal ions such as magnesium and calcium, aswell as zinc and aluminum.

As referred to herein, the term “substituted” means that at least onehydrogen atom (attached to carbon atom or heteroatom) is replaced with anon-hydrogen group, provided that normal valencies are maintained andthat the substitution results in a stable compound. When a substituentis oxo (i.e., ═O), then 2 hydrogens on the atom are replaced. Oxosubstituents are not present on aromatic moieties. When a ring system(e.g., carbocyclic or heterocyclic) is said to be substituted with acarbonyl group or a double bond, it is intended that the carbonyl groupor double bond be part (i.e., within) of the ring. Ring double bonds, asused herein, are double bonds that are formed between two adjacent ringatoms (e.g., C═C, C═N, or N═N). The term “substituted” in reference toalkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, alkylene, aryl,arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, and heterocyclyl,means alkyl, cycloalkyl, heteroalkyl, cyclohetero alkyl, alkylene, aryl,arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, and heterocyclyl,respectively, in which one or more hydrogen atoms, which are attached toeither carbon or heteroatom, are each independently replaced with one ormore non-hydrogen substituent(s).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0, 1, 2, or 3 R groups, then saidgroup be unsubstituted when it is substituted with 0 R group, or besubstituted with up to three R groups, and at each occurrence R isselected independently from the definition of R.

Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

As used herein, the term “tautomer” refers to each of two or moreisomers of a compound that exist together in equilibrium, and arereadily interchanged by migration of an atom or group within themolecule For example, one skilled in the art would readily understandthat a 1,2,3-triazole exists in two tautomeric forms as defined above:

Thus, this disclosure is intended to cover all possible tautomers evenwhen a structure depicts only one of them.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The compounds of the present invention can be present as salts, whichare also within the scope of this invention. Pharmaceutically acceptablesalts are preferred. As used herein, “pharmaceutically acceptable salts”refer to derivatives of the disclosed compounds wherein the parentcompound is modified by making acid or base salts thereof. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton,Pa. (1990), the disclosure of which is hereby incorporated by reference.

If the compounds of the present invention have, for example, at leastone basic center, they can form acid addition salts. These are formed,for example, with strong inorganic acids, such as mineral acids, forexample sulfuric acid, phosphoric acid or a hydrohalic acid, withorganic carboxylic acids, such as alkanecarboxylic acids of 1 to 4carbon atoms, for example acetic acid, which are unsubstituted orsubstituted, for example, by halogen as chloroacetic acid, such assaturated or unsaturated dicarboxylic acids, for example oxalic,malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, suchas hydroxycarboxylic acids, for example ascorbic, glycolic, lactic,malic, tartaric or citric acid, such as amino acids, (for exampleaspartic or glutamic acid or lysine or arginine), or benzoic acid, orwith organic sulfonic acids, such as (C₁-C₄) alkyl or arylsulfonic acidswhich are unsubstituted or substituted, for example by halogen, forexample methyl- or p-toluene- sulfonic acid. Corresponding acid additionsalts can also be formed having, if desired, an additionally presentbasic center. The compounds of the present invention having at least oneacid group (for example COOH) can also form salts with bases. Suitablesalts with bases are, for example, metal salts, such as alkali metal oralkaline earth metal salts, for example sodium, potassium or magnesiumsalts, or salts with ammonia or an organic amine, such as morpholine,thiomorpholine, piperidine, pyrrolidine, a mono, di or tri-loweralkylamine, for example ethyl, tert-butyl, diethyl, diisopropyl,triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxylower alkylamine, for example mono, di or triethanolamine Correspondinginternal salts may furthermore be formed. Salts which are unsuitable forpharmaceutical uses but which can be employed, for example, for theisolation or purification of free compounds of Formula (Ia) or (Ib) ortheir pharmaceutically acceptable salts, are also included. Preferredsalts of the compounds of Formula (Ia) or (Ib) which contain a basicgroup include monohydrochloride, hydrogensulfate, methanesulfonate,phosphate, nitrate or acetate.

Preferred salts of the compounds of Formula (Ia) or (Ib) which containan acid group include sodium, potassium and magnesium salts andpharmaceutically acceptable organic amines

In addition, compounds of Formula (Ia) or (Ib) may have prodrug forms.Any compound that will be converted in vivo to provide the bioactiveagent (i.e., a compound of formula Ia or Ib) is a prodrug within thescope and spirit of the invention. Various forms of prodrugs are wellknown in the art. For examples of such prodrug derivatives, see:

a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder,K. et al., eds., Methods in Enzymology, 112:309-396, Academic Press(1985);

b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”, ATextbook of Drug Design and Development, pp. 113-191, Krosgaard-Larsen,P. et al., eds., Harwood Academic Publishers (1991);

c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);

d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); and

e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

The compounds of the present invention contain a carboxy group which canform physiologically hydrolyzable esters that serve as prodrugs, i.e.,“prodrug esters”, by being hydrolyzed in the body to yield the compoundsof the present invention per se. Examples of physiologicallyhydrolyzable esters of compounds of the present invention include C₁ toC₆ alkyl, C₁ to C₆ alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆ alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl), C₁ to C₆ alkoxycarbonyloxy-C₁to C₆ alkyl (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl,glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art. The “prodrug esters” can be formed byreacting the carboxylic acid moiety of the compounds of the presentinvention with either alkyl or aryl alcohol, halide, or sulfonateemploying procedures known to those skilled in the art. Such esters maybe prepared by conventional techniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al.,Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry andEnzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, Academic Press, San Diego,Calif. (1999).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Deuterium has one proton and one neutron in its nucleus andthat has twice the mass of ordinary hydrogen. Deuterium can berepresented by symbols such as “²H” or “D”. The term “deuterated”herein, by itself or used to modify a compound or group, refers toreplacement of one or more hydrogen atom(s), which is attached tocarbon(s), with a deuterium atom. Isotopes of carbon include ¹³C and¹⁴C.

Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed. Such compounds have a variety of potential uses,e.g., as standards and reagents in determining the ability of apotential pharmaceutical compound to bind to target proteins orreceptors, or for imaging compounds of this invention bound tobiological receptors in vivo or in vitro.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for example,when one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

ABBREVIATIONS

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “RBF”for round bottom flask, “atm” for atmosphere, “psi” for pounds persquare inch, “conc.” for concentrate, “RCM” for ring-closing metathesis,“sat” or “sat′d” for saturated, “SFC” for supercritical fluidchromatography “MW” for molecular weight, “mp” for melting point, “ee”for enantiomeric excess, “MS” or “Mass Spec” for mass spectrometry,“ESI” for electrospray ionization mass spectroscopy, “HR” for highresolution, “HRMS” for high resolution mass spectrometry, “LCMS” forliquid chromatography mass spectrometry, “HPLC” for high pressure liquidchromatography, “RP HPLC” for reverse phase HPLC, “TLC” or “tlc” forthin layer chromatography, “NMR” for nuclear magnetic resonancespectroscopy, “nOe” for nuclear Overhauser effect spectroscopy, “¹H” forproton, “δ” for delta, “s” for singlet, “d” for doublet, “t” fortriplet, “q” for quartet, “m” for multiplet, “br” for broad, “Hz” forhertz, and “α”, “β”, “γ”, “S”, “E”, and “Z” are stereochemicaldesignations familiar to one skilled in the art.

-   Me methyl-   Et ethyl-   Pr propyl-   i-Pr isopropyl-   Bu butyl-   i-Bu isobutyl-   t-Bu tert-butyl-   Ph phenyl-   Bn benzyl-   Boc or BOC tert-butyloxycarbonyl-   Boc₂O di-tert-butyl dicarbonate-   AcOH or HOAc acetic acid-   AlCl₃ aluminum trichloride-   AIBN Azobis-isobutyronitrile-   BBr₃ boron tribromide-   BCl₃ boron trichloride-   BEMP    2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine-   BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate-   Burgess reagent 1-methoxy-N-triethylammoniosulfonyl-methanimidate    CBz carbobenzyloxy-   DCM or CH₂Cl₂ dichloromethane-   CH₃CN or ACN acetonitrile-   CDCl₃ deutero-chloroform-   CHCl₃ chloroform-   mCPBA or m-CPBA meta-chloroperbenzoic acid-   Cs₂CO₃ cesium carbonate-   Cu(OAc)₂ copper (II) acetate-   Cy₂NMe N-cyclohexyl-N-methylcyclohexanamine-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   DCE 1,2 dichloroethane-   DEA Diethylamine-   DEAD Diethyl azodicarboxylate-   Dess-Martin    1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one-   DIAD Diisopropy azodicarboxylate-   DIC or DIPCDI diisopropylcarbodiimide-   DIEA, DIPEA or diisopropylethylamine-   Hunig's base-   DMAP 4-dimethylaminopyridine-   DME 1,2-dimethoxyethane-   DMF dimethyl formamide-   DMSO dimethyl sulfoxide-   cDNA complementary DNA-   Dppp (R)-(+)-1,2-bis(diphenylphosphino)propane-   DuPhos (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene-   EDC N-(3-dimthylaminopropyl)-N′-ethylcarbodiimide-   EDCI N-(3-dimthylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   EDTA ethylenediaminetetraacetic acid-   (S,S)-EtDuPhosRh(I)    (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-cyclooctadiene)rhodium(I)    trifluoromethanesulfonate-   Et₃N or TEA triethylamine-   EtOAc ethyl acetate-   Et₂O diethyl ether-   EtOH ethanol-   GMF glass microfiber filter-   Grubbs II    (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro    (phenylmethylene)(triycyclohexylphosphine)ruthenium-   HCl hydrochloric acid-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HEPES 4-(2-hydroxyethyl)piperaxine-1-ethanesulfonic acid-   Hex hexane-   HOBt or HOBT 1-hydroxybenzotriazole-   H₂O₂ hydrogen peroxide-   IBX 2-iodoxybenzoic acid-   H₂SO₄ sulfuric acid-   Jones reagent CrO₃ in aqueous H₂SO₄, 2 M solution-   K₂CO₃ potassium carbonate-   K₂HPO₄ potassium phosphate dibasic (potassium hydrogen phosphate)-   KOAc potassium acetate-   K₃PO₄ potassium phosphate tribasic-   LAH lithium aluminum hydride-   LG leaving group-   LiOH lithium hydroxide-   MeOH methanol-   MgSO₄ magnesium sulfate-   MsOH or MSA methylsulfonic acid/methanesulfonic acid-   NaCl sodium chloride-   NaH sodium hydride-   NaHCO₃ sodium bicarbonate-   Na₂CO₃ sodium carbonate-   NaOH sodium hydroxide-   Na₂SO₃ sodium sulfite-   Na₂SO₄ sodium sulfate-   NB S N-bromosuccinimide-   NCS N-chlorosuccinimide-   NH₃ ammonia-   NH₄Cl ammonium chloride-   NH₄OH ammonium hydroxide-   NH₄ ⁺HCO₂ ammonium formate-   NMM N-methylmorpholine-   OTf triflate or trifluoromethanesulfonate-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)-   Pd(OAc)₂ palladium(II) acetate-   Pd/C palladium on carbon-   Pd(dppf)Cl₂ [1,1′-bis(diphenylphosphino)-ferrocene]    dichloropalladium(II)-   Ph₃PCl₂ triphenylphosphine dichloride-   PG protecting group-   POCl₃ phosphorus oxychloride-   PPTS pyridinium p-toluenesulfonate-   i-PrOH or IPA isopropanol-   PS Polystyrene-   RT or rt room temperature-   SEM-Cl 2-(trimethysilyl)ethoxymethyl chloride-   SiO₂ silica oxide-   SnCl₂ tin(II) chloride-   TBAF tra-n-butylammonium fluoride-   TBAI tetra-n-butylammonium iodide-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   THP tetrahydropyran-   TMSCHN₂ Trimethylsilyldiazomethane-   TMSCH₂N₃ Trimethylsilylmethyl azide-   T3P propane phosphonic acid anhydride-   TRIS tris (hydroxymethyl) aminomethane-   pTsOH p-toluenesulfonic acid

IV. Biology

Lysophospholipids are membrane-derived bioactive lipid mediators.Lysophospholipids include, but are not limited to, lysophosphatidic acid(1-acyl-2-hydroxy-sn-glycero-3-phosphate; LPA), sphingosine 1-phosphate(S1P), lysophosphatidylcholine (LPC), and sphingosylphosphorylcholine(SPC). Lysophospholipids affect fundamental cellular functions thatinclude cellular proliferation, differentiation, survival, migration,adhesion, invasion, and morphogenesis. These functions influence manybiological processes that include neurogenesis, angiogenesis, woundhealing, immunity, and carcinogenesis.

LPA acts through sets of specific G protein-coupled receptors (GPCRs) inan autocrine and paracrine fashion. LPA binding to its cognate GPCRs(LPA₁, LPA₂, LPA₃, LPA₄, LPA₅, LPA₆) activates intracellular signalingpathways to produce a variety of biological responses.

Lysophospholipids, such as LPA, are quantitatively minor lipid speciescompared to their major phospholipid counterparts (e.g.,phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin). LPAhas a role as a biological effector molecule, and has a diverse range ofphysiological actions such as, but not limited to, effects on bloodpressure, platelet activation, and smooth muscle contraction, and avariety of cellular effects, which include cell growth, cell rounding,neurite retraction, and actin stress fiber formation and cell migration.The effects of LPA are predominantly receptor mediated.

Activation of the LPA receptors (LPA₁, LPA₂, LPA₃, LPA₄, LPA₅, LPA₆)with LPA mediates a range of downstream signaling cascades. Theseinclude, but are not limited to, mitogen-activated protein kinase (MAPK)activation, adenylyl cyclase (AC) inhibition/activation, phospholipase C(PLC) activation/Ca²⁺ mobilization, arachidonic acid release, Akt/PKBactivation, and the activation of small GTPases, Rho, ROCK, Rac, andRas. Other pathways that are affected by LPA receptor activationinclude, but are not limited to, cyclic adenosine monophosphate (cAMP),cell division cycle 42/GTP-binding protein (Cdc42), proto-oncogeneserine/threonine-protein kinase Raf (c-RAF), proto-oncogenetyrosine-protein kinase Src (c-src), extracellular signal-regulatedkinase (ERK), focal adhesion kinase (FAK), guanine nucleotide exchangefactor (GEF), glycogen synthase kinase 3b (GSK3b), c-jun amino-terminalkinase (INK), MEK, myosin light chain II (MLC II), nuclear factor kB(NF-kB), N-methyl-D-aspartate (NMDA) receptor activation,phosphatidylinositol 3-kinase (PI3K), protein kinase A (PKA), proteinkinase C (PKC), ras-related C3 botulinum toxin substrate 1 (RAC1). Theactual pathway and realized end point are dependent on a range ofvariables that include receptor usage, cell type, expression level of areceptor or signaling protein, and LPA concentration. Nearly allmammalian cells, tissues and organs co-express several LPA-receptorsubtypes, which indicates that LPA receptors signal in a cooperativemanner LPA₁, LPA₂, and LPA₃ share high amino acid sequence similarity.

LPA is produced from activated platelets, activated adipocytes, neuronalcells, and other cell types. Serum LPA is produced by multiple enzymaticpathways that involve monoacylglycerol kinase, phospholipase A₁,secretory phospholipase A₂, and lysophospholipase D (lysoPLD), includingautotaxin. Several enzymes are involved in LPA degradation:lysophospholipase, lipid phosphate phosphatase, and LPA acyl transferasesuch as endophilin. LPA concentrations in human serum are estimated tobe 1-5 μM. Serum LPA is bound to albumin, low-density lipoproteins, orother proteins, which possibly protect LPA from rapid degradation. LPAmolecular species with different acyl chain lengths and saturation arenaturally occurring, including 1-palmitoyl (16:0), 1-palmitoleoyl(16:1), 1-stearoyl (18:0), 1-oleoyl (18:1), 1-linoleoyl (18:2), and1-arachidonyl (20:4) LPA. Quantitatively minor alkyl LPA has biologicalactivities similar to acyl LPA, and different LPA species activate LPAreceptor subtypes with varied efficacies.

LPA Receptors

LPA₁ (previously called VZG-1/EDG-2/mrec1.3) couples with three types ofG proteins, G_(i/o), G_(q), and G_(12/13). Through activation of these Gproteins, LPA induces a range of cellular responses through LPA₁including but not limited to: cell proliferation, serum-response element(SRE) activation, mitogen-activated protein kinase (MAPK) activation,adenylyl cyclase (AC) inhibition, phospholipase C (PLC) activation, Ca²⁺mobilization, Akt activation, and Rho activation.

Wide expression of LPA₁ is observed in adult mice, with clear presencein testis, brain, heart, lung, small intestine, stomach, spleen, thymus,and skeletal muscle. Similarly, human tissues also express LPA₁; it ispresent in brain, heart, lung, placenta, colon, small intestine,prostate, testis, ovary, pancreas, spleen, kidney, skeletal muscle, andthymus.

LPA₂ (EDG-4) also couples with three types of G proteins, G_(i/o),G_(q), and G_(12/13), to mediate LPA-induced cellular signaling.Expression of LPA₂ is observed in the testis, kidney, lung, thymus,spleen, and stomach of adult mice and in the human testis, pancreas,prostate, thymus, spleen, and peripheral blood leukocytes. Expression ofLPA₂ is upregulated in various cancer cell lines, and several human LPA₂transcriptional variants with mutations in the 3′-untranslated regionhave been observed. Targeted deletion of LPA₂ in mice has not shown anyobvious phenotypic abnormalities, but has demonstrated a significantloss of normal LPA signaling (e.g., PLC activation, Ca²⁺ mobilization,and stress fiber formation) in primary cultures of mouse embryonicfibroblasts (MEFs). Creation of Ipa1(−/−) Ipa2 (−/−) double-null micehas revealed that many LPA-induced responses, which include cellproliferation, AC inhibition, PLC activation, Ca²⁺ mobilization, JNK andAkt activation, and stress fiber formation, are absent or severelyreduced in double-null MEFs. All these responses, except for ACinhibition (AC inhibition is nearly abolished in LPA₁ (−/−) MEFs), areonly partially affected in either LPA₁ (−/−) or LPA₂ (−/−) MEFs. LPA₂contributes to normal LPA-mediated signaling responses in at least somecell types (Choi et al, Biochemica et Biophysica Acta 2008, 1781, p531-539).

LPA₃ (EDG-7) is distinct from LPA₁ and LPA₂ in its ability to couplewith G_(i/o) and G_(q) but not G_(12/13) and is much less responsive toLPA species with saturated acyl chains. LPA₃ can mediate pleiotropicLPA-induced signaling that includes PLC activation, Ca²⁺ mobilization,AC inhibition/activation, and MAPK activation. Overexpression of LPA₃ inneuroblastoma cells leads to neurite elongation, whereas that of LPA₁ orLPA₂ results in neurite retraction and cell rounding when stimulatedwith LPA. Expression of LPA₃ is observed in adult mouse testis, kidney,lung, small intestine, heart, thymus, and brain. In humans, it is foundin the heart, pancreas, prostate, testis, lung, ovary, and brain(frontal cortex, hippocampus, and amygdala).

LPA₄ (p2y₉/GPR23) is of divergent sequence compared to LPA₁, LPA₂, andLPA₃ with closer similarity to the platelet-activating factor (PAF)receptor. LPA₄ mediates LPA induced Ca²⁺ mobilization and cAMPaccumulation, and functional coupling to the G protein Gs for ACactivation, as well as coupling to other G proteins. The LPA₄ gene isexpressed in the ovary, pancreas, thymus, kidney and skeletal muscle.

LPA₅ (GPR92) is a member of the purinocluster of GPCRs and isstructurally most closely related to LPA₄. LPA₅ is expressed in humanheart, placenta, spleen, brain, lung and gut. LPA₅ also shows very highexpression in the CD8+ lymphocyte compartment of the gastrointestinaltract.

LPA₆ (p2y5) is a member of the purinocluster of GPCRs and isstructurally most closely related to LPA₄. LPA₆ is an LPA receptorcoupled to the G12/13-Rho signaling pathways and is expressed in theinner root sheaths of human hair follicles.

Illustrative Biological Activity

Wound Healing

Normal wound healing occurs by a highly coordinated sequence of eventsin which cellular, soluble factors and matrix components act in concertto repair the injury. The healing response can be described as takingplace in four broad, overlapping phases—hemostasis, inflammation,proliferation, and remodeling. Many growth factors and cytokines arereleased into a wound site to initiate and perpetuate wound healingprocesses.

When wounded, damaged blood vessels activate platelets. The activatedplatelets play pivotal roles in subsequent repair processes by releasingbioactive mediators to induce cell proliferation, cell migration, bloodcoagulation, and angiogenesis. LPA is one such mediator that is releasedfrom activated platelets; this induces platelet aggregation along withmitogenic/migration effects on the surrounding cells, such asendothelial cells, smooth muscle cells, fibroblasts, and keratinocytes.

Topical application of LPA to cutaneous wounds in mice promotes repairprocesses (wound closure and increased neoepithelial thickness) byincreasing cell proliferation/migration without affecting secondaryinflammation.

Activation of dermal fibroblasts by growth factors and cytokines leadsto their subsequent migration from the edges of the wound into theprovisional matrix formed by the fibrin clot whereupon the fibroblastsproliferate and start to restore the dermis by secreting and organizingthe characteristic dermal extracellular matrix (ECM). The increasingnumber of fibroblasts within the wound and continuous precipitation ofECM enhances matrix rigidity by applying small tractional forces to thenewly formed granulation tissue. The increase in mechanical stress, inconjunction with transforming growth factor β (TGFβ), induces α-smoothmuscle actin (α-SMA) expression and the subsequent transformation offibroblasts into myofibroblasts. Myofibroblasts facilitate granulationtissue remodeling via myofibroblast contraction and through theproduction of ECM components.

LPA regulates many important functions of fibroblasts in wound healing,including proliferation, migration, differentiation and contraction.Fibroblast proliferation is required in wound healing in order to fillan open wound. In contrast, fibrosis is characterized by intenseproliferation and accumulation of myofibroblasts that activelysynthesize ECM and proinflammatory cytokines. LPA can either increase orsuppress the proliferation of cell types important in wound healing,such as epithelial and endothelial cells (EC), macrophages,keratinocytes, and fibroblasts. A role for LPA₁ in LPA-inducedproliferation was provided by the observation that LPA-stimulatedproliferation of fibroblasts isolated from LPA₁ receptor null mice wasattenuated (Mills et al, Nat Rev. Cancer 2003; 3: 582-591). LPA inducescytoskeletal changes that are integral to fibroblast adhesion,migration, differentiation and contraction.

Fibrosis

Tissue injury initiates a complex series of host wound-healingresponses; if successful, these responses restore normal tissuestructure and function. If not, these responses can lead to tissuefibrosis and loss of function.

For the majority of organs and tissues the development of fibrosisinvolves a multitude of events and factors. Molecules involved in thedevelopment of fibrosis include proteins or peptides (profibroticcytokines, chemokines, metalloproteinases etc.) and phospholipids.Phospholipids involved in the development of fibrosis include plateletactivating factor (PAF), phosphatidyl choline, sphingosine-1 phosphate(S1P) and lysophosphatidic acid (LPA).

A number of muscular dystrophies are characterized by a progressiveweakness and wasting of musculature, and by extensive fibrosis. It hasbeen shown that LPA treatment of cultured myoblasts induced significantexpression of connective tissue growth factor (CTGF). CTGF subsequentlyinduces collagen, fibronectin and integrin expression and inducesdedifferentiation of these myoblasts. Treatment of a variety of celltypes with LPA induces reproducible and high level induction of CTGF (J.P. Pradere, et al., LPA₁ receptor activation promotes renal interstitialfibrosis, J. Am. Soc. Nephrol. 18 (2007) 3110-3118; N. Wiedmaier, etal., Int J Med Microbiol; 298(3-4):231-43, 2008). CTGF is a profibroticcytokine, signaling down-stream and in parallel with TGFβ.

CTGF expression by gingival epithelial cells, which are involved in thedevelopment of gingival fibromatosis, was found to be exacerbated by LPAtreatment (A. Kantarci, et al., J. Pathol. 210 (2006) 59-66).

LPA is associated with the progression of liver fibrosis. In vitro, LPAinduces stellate cell and hepatocyte proliferation. These activatedcells are the main cell type responsible for the accumulation of ECM inthe liver. Furthermore, LPA plasma levels rise during CCl₄-induced liverfibrosis in rodents, or in hepatitis C virus-induced liver fibrosis inhumans (N. Watanabe, et al., Plasma lysophosphatidic acid level andserum autotaxin activity are increased in liver injury in rats inrelation to its severity, Life Sci. 81 (2007) 1009-1015; N. Watanabe, etal., J. Clin. Gastroenterol. 41 (2007) 616-623).

An increase of phospholipid concentrations in the bronchoalveolar lavagefluid in rabbits and rodents injected with bleomycin has been reported(K. Kuroda, et al., Phospholipid concentration in lung lavage fluid asbiomarker for pulmonary fibrosis, Inhal. Toxicol. 18 (2006) 389-393; K.Yasuda, et al., Lung 172 (1994) 91-102).

LPA is associated with heart disease and mycocardial remodeling. SerumLPA levels are increased after myocardial infarction in patients and LPAstimulates rat cardiac fibroblast proliferation and collagen production(Chen et al. FEBS Lett. 2006 Aug. 21; 580(19):4737-45).

Pulmonary Fibrosis

In the lung, aberrant wound healing responses to injury contribute tothe pathogenesis of fibrotic lung diseases. Fibrotic lung diseases, suchas idiopathic pulmonary fibrosis (IPF), are associated with highmorbidity and mortality.

LPA is an important mediator of fibroblast recruitment in pulmonaryfibrosis. LPA and LPA₁ play key pathogenic roles in pulmonary fibrosis.Fibroblast chemoattractant activity plays an important role in the lungsin patients with pulmonary fibrosis. Profibrotic effects ofLPA₁-receptor stimulation is explained by LPA₁-receptor-mediatedvascular leakage and increased fibroblast recruitment, both profibroticevents. The LPA-LPA₁ pathway has a role in mediating fibroblastmigration and vascular leakage in IPF. The end result is the aberranthealing process that characterizes this fibrotic condition.

The LPA₁ receptor is the LPA receptor most highly expressed onfibroblasts obtained from patients with IPF. Furthermore, BAL obtainedfrom IPF patients induced chemotaxis of human foetal lung fibroblaststhat was blocked by the dual LPA₁-LPA₃ receptor antagonist Ki16425. Inan experimental bleomycin-induced lung injury mouse model, it was shownthat LPA levels were high in bronchoalveolar lavage samples comparedwith unexposed controls. LPA₁ knockout mice are protected from fibrosisafter bleomycin challenge with reduced fibroblast accumulation andvascular leakage. In human subjects with IPF, high LPA levels wereobserved in bronchoalveolar lavage samples compared with healthycontrols. Increased fibroblast chemotactic activity in these samples wasinhibited by the Ki16425 indicating that fibroblast migration ismediated by the LPA-LPA receptor(s) pathway (Tager et al. NatureMedicine, 2008, 14, 45-54).

The LPA-LPA₁ pathway is crucial in fibroblast recruitment and vascularleakage in pulmonary fibrosis.

Activation of latent TGF-β by the αvβ6 integrin plays a critical role inthe development of lung injury and fibrosis (Munger et al. Cell, vol.96, 319-328, 1999). LPA induces αvβ6-mediated TGF-β activation on humanlung epithelial cells (Xu et al. Am. J. Pathology, 2009, 174,1264-1279). The LPA-induced αvβ6-mediated TGF-β activation is mediatedby the LPA₂ receptor. Expression of the LPA₂ receptor is increased inepithelial cells and mesenchymal cells in areas of lung fibrosis fromIPF patients compared to normal human lung tissue. The LPA-LPA₂ pathwaycontributes to the activation of the TGF-β pathway in pulmonaryfibrosis. In some embodiments, compounds that inhibit LPA₂ show efficacyin the treatment of lung fibrosis. In some embodiments, compounds thatinhibit both LPA₁ and LPA₂ show improved efficacy in the treatment oflung fibrosis compared to compounds which inhibit only LPA₁ or LPA₂.

The LPA₁ antagonist BMS-986020 was shown to significantly reduce therate of FVC (forced vital capacity) decline in a 26-week clinical trialin IPF patients (Palmer et al., Chest, 2018, 154, 1061-1069).

Renal Fibrosis

LPA and LPA₁ are involved in the etiology of kidney fibrosis. LPA haseffects on both proliferation and contraction of glomerular mesangialcells and thus has been implicated in proliferative glomerulonephritis(C. N. Inoue, et al., Clin. Sci. (Colch.) 1999, 96, 431-436). In ananimal model of renal fibrosis [unilateral ureteral obstruction (UUO)],it was found that renal LPA receptors are expressed under basalconditions with an expression order of LPA₂>LPA₃=LPA₁>>LPA₄. This modelmimics in an accelerated manner the development of renal fibrosisincluding renal inflammation, fibroblast activation and accumulation ofextracellular matrix in the tubulointerstitium. UUO significantlyinduced LPA₁-receptor expression. This was paralleled by renal LPAproduction (3.3 fold increase) in conditioned media from kidneyexplants. Contra-lateral kidneys exhibited no significant changes in LPArelease and LPA-receptors expression. This shows that a prerequisite foran action of LPA in fibrosis is met: production of a ligand (LPA) andinduction of one of its receptors (the LPA₁ receptor) (J. P. Pradere etal., Biochimica et Biophysica Acta, 2008, 1781, 582-587).

In mice where the LPA₁ receptor was knocked out (LPA₁ (−/−), thedevelopment of renal fibrosis was significantly attenuated. UUO micetreated with the LPA receptor antagonist Ki16425 closely resembled theprofile of LPA₁ (−/−) mice.

LPA can participate in intraperitonial accumulation ofmonocyte/macrophages and LPA can induce expression of the profibroticcytokine CTGF in primary cultures of human fibroblasts (J. S. Koh, etal., J. Clin. Invest., 1998, 102, 716-727).

LPA treatment of a mouse epithelial renal cell line, MCT, induced arapid increase in the expression of the profibrotic cytokine CTGF. CTGFplays a crucial role in UUO-induced tubulointerstitial fibrosis (TIF),and is involved in the profibrotic activity of TGFβ. This induction wasalmost completely suppressed by co-treatment with the LPA-receptorantagonist Ki16425. In one aspect, the profibrotic activity of LPA inkidney results from a direct action of LPA on kidney cells involvinginduction of CTGF.

Hepatic Fibrosis

LPA is implicated in liver disease and fibrosis. Plasma LPA levels andserum autotaxin (enzyme responsible for LPA production) are elevated inhepatitis patients and animal models of liver injury in correlation withincreased fibrosis. LPA also regulates liver cell function. LPA₁ andLPA₂ receptors are expressed by mouse hepatic stellate cells and LPAstimulates migration of hepatic myofibroblasts.

Ocular Fibrosis

LPA is in involved in wound healing in the eye. LPA₁ and LPA₃ receptorsare detectable in the normal rabbit corneal epithelial cells,keratocytes and endothelial cells and LPA₁ and LPA₃ expression areincreased in corneal epithelial cells following injury.

LPA and its homologues are present in the aqueous humor and the lacrimalgland fluid of the rabbit eye and these levels are increased in a rabbitcorneal injury model.

LPA induces actin stress fiber formation in rabbit corneal endothelialand epithelial cells and promotes contraction corneal fibroblasts. LPAalso stimulates proliferation of human retinal pigmented epithelialcells

Cardiac Fibrosis

LPA is implicated in myocardial infarction and cardiac fibrosis. SerumLPA levels are increased in patients following mycocardial infarction(MI) and LPA stimulates proliferation and collagen production (fibrosis)by rat cardiac fibroblasts. Both LPA1 and LPA3 receptors are highlyexpressed in human heart tissue.

Treatment of Fibrosis

In one aspect, a compound of Formula (Ia) or (Ib), or a pharmaceuticallyacceptable salt or solvate thereof, is used to treat or prevent fibrosisin a mammal. In one aspect, a compound of Formula (Ia) or (Ib), or apharmaceutically acceptable salt or solvate thereof, is used to treatfibrosis of an organ or tissue in a mammal. In one aspect is a methodfor preventing a fibrosis condition in a mammal, the method comprisingadministering to the mammal at risk of developing one or more fibrosisconditions a therapeutically effective amount of a compound of Formula(Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof.In one aspect, the mammal has been exposed to one or more environmentalconditions that are known to increase the risk of fibrosis of an organor tissue. In one aspect, the mammal has been exposed to one or moreenvironmental conditions that are known to increase the risk of lung,liver or kidney fibrosis. In one aspect, the mammal has a geneticpredisposition of developing fibrosis of an organ or tissue. In oneaspect, a compound of Formula (Ia) or (Ib), or a pharmaceuticallyacceptable salt or solvate thereof, is administered to a mammal toprevent or minimize scarring following injury. In one aspect, injuryincludes surgery.

The terms “fibrosis” or “fibrosing disorder,” as used herein, refers toconditions that are associated with the abnormal accumulation of cellsand/or fibronectin and/or collagen and/or increased fibroblastrecruitment and include but are not limited to fibrosis of individualorgans or tissues such as the heart, kidney, liver, joints, lung,pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletaland digestive tract.

Exemplary diseases, disorders, or conditions that involve fibrosisinclude, but are not limited to: Lung diseases associated with fibrosis,e.g., idiopathic pulmonary fibrosis, pulmonary fibrosis secondary tosystemic inflammatory disease such as rheumatoid arthritis, scleroderma,lupus, cryptogenic fibrosing alveolitis, radiation induced fibrosis,chronic obstructive pulmonary disease (COPD), scleroderma, chronicasthma, silicosis, asbestos induced pulmonary or pleural fibrosis, acutelung injury and acute respiratory distress (including bacterialpneumonia induced, trauma induced, viral pneumonia induced, ventilatorinduced, non-pulmonary sepsis induced, and aspiration induced); Chronicnephropathies associated with injury/fibrosis (kidney fibrosis), e.g.,glomerulonephritis secondary to systemic inflammatory diseases such aslupus and scleroderma, diabetes, glomerular nephritis, focal segmentalglomerular sclerosis, IgA nephropathy, hypertension, allograft andAlport; Gut fibrosis, e.g., scleroderma, and radiation induced gutfibrosis; Liver fibrosis, e.g., cirrhosis, alcohol induced liverfibrosis, nonalcoholic steatohepatitis (NASH), biliary duct injury,primary biliary cirrhosis, infection or viral induced liver fibrosis(e.g., chronic HCV infection), and autoimmune hepatitis; Head and neckfibrosis, e.g., radiation induced; Corneal scarring, e.g., LASIK(laser-assisted in situ keratomileusis), corneal transplant, andtrabeculectomy; Hypertrophic scarring and keloids, e.g., burn induced orsurgical; and other fibrotic diseases, e.g., sarcoidosis, scleroderma,spinal cord injury/fibrosis, myelofibrosis, vascular restenosis,atherosclerosis, arteriosclerosis, Wegener's granulomatosis, mixedconnective tissue disease, and Peyronie's disease.

In one aspect, a mammal suffering from one of the following non-limitingexemplary diseases, disorders, or conditions will benefit from therapywith a compound of Formula (Ia) or (Ib), or a pharmaceuticallyacceptable salt or solvate thereof: atherosclerosis, thrombosis, heartdisease, vasculitis, formation of scar tissue, restenosis, phlebitis,COPD (chronic obstructive pulmonary disease), pulmonary hypertension,pulmonary fibrosis, pulmonary inflammation, bowel adhesions, bladderfibrosis and cystitis, fibrosis of the nasal passages, sinusitis,inflammation mediated by neutrophils, and fibrosis mediated byfibroblasts.

In one aspect, a compound of Formula (Ia) or (Ib), or a pharmaceuticallyacceptable salt or solvate thereof, is administered to a mammal withfibrosis of an organ or tissue or with a predisposition of developingfibrosis of an organ or tissue with one or more other agents that areused to treat fibrosis. In one aspect, the one or more agents includecorticosteroids. In one aspect, the one or more agents includeimmunosuppressants. In one aspect, the one or more agents include B-cellantagonists. In one aspect, the one or more agents include uteroglobin.

In one aspect, a compound of Formula (Ia) or (Ib), or a pharmaceuticallyacceptable salt or solvate thereof, is used to treat a dermatologicaldisorders in a mammal. The term “dermatological disorder,” as usedherein refers to a skin disorder. Such dermatological disorders include,but are not limited to, proliferative or inflammatory disorders of theskin such as, atopic dermatitis, bullous disorders, collagenoses,psoriasis, scleroderma, psoriatic lesions, dermatitis, contactdermatitis, eczema, urticaria, rosacea, wound healing, scarring,hypertrophic scarring, keloids, Kawasaki Disease, rosacea,Sjogren-Larsso Syndrome, urticaria. In one aspect, a compound of Formula(Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof,is used to treat systemic sclerosis.

Pain

Since LPA is released following tissue injury, LPA₁ plays an importantrole in the initiation of neuropathic pain. LPA₁, unlike LPA₂ or LPA₃,is expressed in both dorsal root ganglion (DRG) and dorsal root neurons.Using the antisense oligodeoxynucleotide (AS-ODN) for LPA₁ and LPA₁-nullmice, it was found that LPA-induced mechanical allodynia andhyperalgesia is mediated in an LPA₁-dependent manner. LPA₁ anddownstream Rho-ROCK activation play a role in the initiation ofneuropathic pain signaling. Pretreatment with Clostridium botulinum C3exoenzyme (BoTXC3, Rho inhibitor) or Y-27632 (ROCK inhibitor) completelyabolished the allodynia and hyperalgesia in nerve-injured mice. LPA alsoinduced demyelination of the dorsal root, which was prevented by BoTXC3.The dorsal root demyelination by injury was not observed in LPA₁-nullmice or AS-ODN injected wild-type mice. LPA signaling appears to induceimportant neuropathic pain markers such as protein kinase Cγ (PKCγ) anda voltage-gated calcium channel α2δ1 subunit (Caα2δ1) in an LPA₁ andRho-dependent manner (M. Inoue, et al., Initiation of neuropathic painrequires lysophosphatidic acid receptor signaling, Nat. Med. 10 (2004)712-718).

In one aspect, a compound of Formula (Ia) or (Ib), or a pharmaceuticallyacceptable salt or solvate thereof, is used in the treatment of pain ina mammal. In one aspect, the pain is acute pain or chronic pain. Inanother aspect, the pain is neuropathic pain.

In one aspect, a compound of Formula (Ia) or (Ib), or a pharmaceuticallyacceptable salt or solvate thereof, is used in the treatment offibromylagia. In one aspect, fibromyalgia stems from the formation offibrous scar tissue in contractile (voluntary) muscles. Fibrosis bindsthe tissue and inhibits blood flow, resulting in pain.

Cancer

Lysophospholipid receptor signaling plays a role in the etiology ofcancer. Lysophosphatidic acid (LPA) and its G protein-coupled receptors(GPCRs) LPA₁, LPA₂, and/or LPA₃ play a role in the development ofseveral types of cancers. The initiation, progression and metastasis ofcancer involve several concurrent and sequential processes includingcell proliferation and growth, survival and anti-apoptosis, migration ofcells, penetration of foreign cells into defined cellular layers and/ororgans, and promotion of angiogenesis. The control of each of theseprocesses by LPA signaling in physiological and pathophysiologicalconditions underscores the potential therapeutic usefulness ofmodulating LPA signaling pathways for the treatment of cancer,especially at the level of the LPA receptors or ATX/lysoPLD. Autotaxin(ATX) is a prometastatic enzyme initially isolated from the conditionedmedium of human melanoma cells that stimulates a myriad of biologicalactivities, including angiogenesis and the promotion of cell growth,migration, survival, and differentiation through the production of LPA(Mol Cancer Ther 2008; 7(10):3352-62).

LPA signals through its own GPCRs leading to activation of multipledownstream effector pathways. Such downstream effector pathways play arole in cancer. LPA and its GPCRs are linked to cancer through majoroncogenic signaling pathways.

LPA contributes to tumorigenesis by increasing motility and invasivenessof cells. LPA has been implicated in the initiation or progression ofovarian cancer. LPA is present at significant concentrations (2-80 μM)in the ascitic fluid of ovarian cancer patients. Ovarian cancer cellsconstitutively produce increased amounts of LPA as compared to normalovarian surface epithelial cells, the precursor of ovarian epithelialcancer. Elevated LPA levels are also detected in plasma from patientswith early-stage ovarian cancers compared with controls. LPA receptors(LPA₂ and LPA₃) are also overexpressed in ovarian cancer cells ascompared to normal ovarian surface epithelial cells. LPA stimulatesCox-2 expression through transcriptional activation andpost-transcriptional enhancement of Cox-2 mRNA in ovarian cancer cells.Prostaglandins produced by Cox-2 have been implicated in a number ofhuman cancers and pharmacological inhibition of Cox-2 activity reducescolon cancer development and decreases the size and number of adenomasin patients with familial adenomatous polyposis. LPA has also beenimplicated in the initiation or progression of prostate cancer, breastcancer, melanoma, head and neck cancer, bowel cancer (colorectalcancer), thyroid cancer and other cancers (Gardell et al, Trends inMolecular Medicine, vol. 12, no. 2, p 65-75, 2006; Ishii et al, Annu.Rev. Biochem, 73, 321-354, 2004; Mills et al., Nat. Rev. Cancer, 3,582-591, 2003; Murph et al., Biochimica et Biophysica Acta, 1781,547-557, 2008).

The cellular responses to LPA are mediated through the lysophosphatidicacid receptors. For example, LPA receptors mediate both migration of andinvasion by pancreatic cancer cell lines: an antagonist of LPA₁ and LPA₃(Ki16425) and LPA₁-specific siRNA effectively blocked in vitro migrationin response to LPA and peritoneal fluid (ascites) from pancreatic cancerpatients; in addition, Ki16425 blocked the LPA-induced andascites-induced invasion activity of a highly peritoneal metastaticpancreatic cancer cell line (Yamada et al, J. Biol. Chem., 279,6595-6605, 2004).

Colorectal carcinoma cell lines show significant expression of LPA₁ mRNAand respond to LPA by cell migration and production of angiogenicfactors. Overexpression of LPA receptors has a role in the pathogenesisof thyroid cancer. LPA₃ was originally cloned from prostate cancercells, concordant with the ability of LPA to induce autocrineproliferation of prostate cancer cells.

LPA has stimulatory roles in cancer progression in many types of cancer.LPA is produced from and induces proliferation of prostate cancer celllines. LPA induces human colon carcinoma DLD1 cell proliferation,migration, adhesion, and secretion of angiogenic factors through LPA₁signaling. In other human colon carcinoma cells lines (HT29 and WiDR),LPA enhances cell proliferation and secretion of angiogenic factors. Inother colon cancer cell lines, LPA₂ and LPA₃ receptor activation resultsin proliferation of the cells. The genetic or pharmacologicalmanipulation of LPA metabolism, specific blockade of receptor signaling,and/or inhibition of downstream signal transduction pathways, representapproaches for cancer therapies.

It has been reported that LPA and other phospholipids stimulateexpression of interleukin-8 (IL-8) in ovarian cancer cell lines. In someembodiments, high concentrations of IL-8 in ovarian cancer correlatewith poor initial response to chemotherapy and with poor prognosis,respectively. In animal models, expression of IL-8 and other growthfactors such as vascular endothelial growth factor (VEGF) is associatedwith increased tumorigenicity, ascites formation, angiogenesis, andinvasiveness of ovarian cancer cells. In some aspects, IL-8 is animportant modulator of cancer progression, drug resistance, andprognosis in ovarian cancer. In some embodiments, a compound of Formula(Ia) or (Ib) inhibits or reduces IL-8 expression in ovarian cancer celllines.

In one aspect, a compound of Formula (Ia) or (Ib), or a pharmaceuticallyacceptable salt or solvate thereof, is used in the treatment of cancer.In one aspect, a compound of Formula (Ia) or (Ib), or a pharmaceuticallyacceptable salt or solvate thereof, is used in the treatment ofmalignant and benign proliferative disease. In one aspect, a compound ofFormula (Ia) or (Ib), or a pharmaceutically acceptable salt or solvatethereof, is used to prevent or reduce proliferation of tumor cells,invasion and metastasis of carcinomas, pleural mesothelioma (Yamada,Cancer Sci., 2008, 99(8), 1603-1610) or peritoneal mesothelioma, cancerpain, bone metastases (Boucharaba et al, J. Clin. Invest., 2004,114(12), 1714-1725; Boucharaba et al, Proc. Natl. acad. Sci., 2006,103(25) 9643-9648). In one aspect is a method of treating cancer in amammal, the method comprising administering to the mammal a compound ofFormula (Ia) or (Ib), or a pharmaceutically acceptable salt or solvatethereof, and a second therapeutic agent, wherein the second therapeuticagent is an anti-cancer agent.

The term “cancer,” as used herein refers to an abnormal growth of cellswhich tend to proliferate in an uncontrolled way and, in some cases, tometastasize (spread). The types of cancer include, but is not limitedto, solid tumors (such as those of the bladder, bowel, brain, breast,endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary,pancreas or other endocrine organ (thyroid), prostate, skin (melanoma orbasal cell cancer) or hematological tumors (such as the leukemias) atany stage of the disease with or without metastases.

Additional non-limiting examples of cancers include, acute lymphoblasticleukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer,appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basalcell carcinoma, bile duct cancer, bladder cancer, bone cancer(osteosarcoma and malignant fibrous histiocytoma), brain stem glioma,brain tumors, brain and spinal cord tumors, breast cancer, bronchialtumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia,chronic myelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cutaneous T-Cell lymphoma, embryonal tumors,endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer,ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladdercancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumor (GIST), gastrointestinal stromal celltumor, germ cell tumor, glioma, hairy cell leukemia, head and neckcancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngealcancer, intraocular melanoma, islet cell tumors (endocrine pancreas),Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngealcancer, leukemia, Acute lymphoblastic leukemia, acute myeloid leukemia,chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cellleukemia, liver cancer, non-small cell lung cancer, small cell lungcancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma,non-Hodgkin lymphoma, lymphoma, Waldenström macroglobulinemia,medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouthcancer, chronic myelogenous leukemia, myeloid leukemia, multiplemyeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma,non-small cell lung cancer, oral cancer, oropharyngeal cancer,osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer,ovarian epithelial cancer, ovarian germ cell tumor, ovarian lowmalignant potential tumor, pancreatic cancer, papillomatosis,parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymaltumors of intermediate differentiation, pineoblastoma and supratentorialprimitive neuroectodermal tumors, pituitary tumor, plasma cellneoplasm/multiple myeloma, pleuropulmonary blastoma, primary centralnervous system lymphoma, prostate cancer, rectal cancer, renal cell(kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary glandcancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, kaposi, Sézarysyndrome, skin cancer, small cell Lung cancer, small intestine cancer,soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer,supratentorial primitive neuroectodermal tumors, T-cell lymphoma,testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroidcancer, urethral cancer, uterine cancer, uterine sarcoma, vaginalcancer, vulvar cancer, Waldenström macroglobulinemia, Wilms tumor.

The increased concentrations of LPA and vesicles in ascites from ovariancancer patients and breast cancer effussions indicate that it could bean early diagnostic marker, a prognostic indicator or an indicator ofresponse to therapy (Mills et al, Nat. Rev. Cancer., 3, 582-591, 2003;Sutphen et al., Cancer Epidemiol. Biomarkers Prev. 13, 1185-1191, 2004).LPA concentrations are consistently higher in ascites samples than inmatched plasma samples.

Respiratory and Allergic Disorders

In one aspect, LPA is a contributor to the pathogenesis of respiratorydiseases. In one aspect the respiratory disease is asthma.Proinflammatory effects of LPA include degranulation of mast cells,contraction of smooth-muscle cells and release of cytokines fromdendritic cells. Airway smooth muscle cells, epithelial cells and lungfibroblasts all show responses to LPA. LPA induces the secretion of IL-8from human bronchial epithelial cells. IL-8 is found in increasedconcentrations in BAL fluids from patients with asthma, chronicobstructive lung disease, pulmonary sarcoidosis and acute respiratorydistress syndrome and 11-8 has been shown to exacerbate airwayinflammation and airway remodeling of asthmatics. LPA₁, LPA₂ and LPA₃receptors have all been shown to contribute to the LPA-induced IL-8production. Studies cloning multiple GPCRs that are activated by LPAallowed the demonstration of the presence of mRNA for the LPA₁, LPA₂ andLPA₃ in the lung (J. J. A. Contos, et al., Mol. Pharmacol. 58,1188-1196, 2000).

The release of LPA from platelets activated at a site of injury and itsability to promote fibroblast proliferation and contraction are featuresof LPA as a mediator of wound repair. In the context of airway disease,asthma is an inflammatory disease where inappropriate airway “repair”processes lead to structural “remodeling” of the airway. In asthma, thecells of the airway are subject to ongoing injury due to a variety ofinsults, including allergens, pollutants, other inhaled environmentalagents, bacteria and viruses, leading to the chronic inflammation thatcharacterizes asthma.

In one aspect, in the asthmatic individual, the release of normal repairmediators, including LPA, is exaggerated or the actions of the repairmediators are inappropriately prolonged leading to inappropriate airwayremodeling. Major structural features of the remodeled airway observedin asthma include a thickened lamina reticularis (the basementmembrane-like structure just beneath the airway epithelial cells),increased numbers and activation of myofibroblasts, thickening of thesmooth muscle layer, increased numbers of mucus glands and mucussecretions, and alterations in the connective tissue and capillary bedthroughout the airway wall. In one aspect, LPA contributes to thesestructural changes in the airway. In one aspect, LPA is involved inacute airway hyperresponsiveness in asthma. The lumen of the remodeledasthmatic airway is narrower due to the thickening of the airway wall,thus decreasing airflow. In one aspect, LPA contributes to the long-termstructural remodeling and the acute hyperresponsiveness of the asthmaticairway. In one aspect, LPA contributes to the hyper-responsiveness thatis a primary feature of acute exacerbations of asthma.

In addition to the cellular responses mediated by LPA, several of theLPA signaling pathway components leading to these responses are relevantto asthma. EGF receptor upregulation is induced by LPA and is also seenin asthmatic airways (M. Amishima, et al., Am. J. Respir. Crit. CareMed. 157, 1907-1912, 1998). Chronic inflammation is a contributor toasthma, and several of the transcription factors that are activated byLPA are known to be involved in inflammation (Ediger et al., Eur RespirJ 21:759-769, 2003).

In one aspect, the fibroblast proliferation and contraction andextracellular matrix secretion stimulated by LPA contributes to thefibroproliferative features of other airway diseases, such as theperibronchiolar fibrosis present in chronic bronchitis, emphysema, andinterstitial lung disease. Emphysema is also associated with a mildfibrosis of the alveolar wall, a feature which is believed to representan attempt to repair alveolar damage. In another aspect, LPA plays arole in the fibrotic interstitial lung diseases and obliterativebronchiolitis, where both collagen and myofibroblasts are increased. Inanother aspect, LPA is involved in several of the various syndromes thatconstitute chronic obstructive pulmonary disease.

Administration of LPA in vivo induces airway hyper-responsiveness,itch-scratch responses, infiltration and activation of eosinophils andneutrophils, vascular remodeling, and nociceptive flexor responses. LPAalso induces histamine release from mouse and rat mast cells. In anacute allergic reaction, histamine induces various responses, such ascontraction of smooth muscle, plasma exudation, and mucus production.Plasma exudation is important in the airway, because the leakage andsubsequent airway-wall edema contribute to the development of airwayhyperresponsiveness. Plasma exudation progresses to conjunctivalswelling in ocular allergic disorder and nasal blockage in allergicrhinitis (Hashimoto et al., J Pharmacol Sci 100, 82-87, 2006). In oneaspect, plasma exudation induced by LPA is mediated by histamine releasefrom mast cells via one or more LPA receptors. In one aspect, the LPAreceptor(s) include LPA₁ and/or LPA₃. In one aspect, a compound ofFormula (Ia) or (Ib), or a pharmaceutically acceptable salt or solvatethereof, is used in the treatment of various allergic disorders in amammal. In one aspect, a compound of Formula (Ia) or (Ib), or apharmaceutically acceptable salt or solvate thereof, is used in thetreatment of respiratory diseases, disorders or conditions in a mammal.In one aspect, a compound of Formula (Ia) or (Ib), or a pharmaceuticallyacceptable salt or solvate thereof, is used in the treatment of asthmain a mammal. In one aspect, a compound of Formula (Ia) or (Ib), or apharmaceutically acceptable salt or solvate thereof, is used in thetreatment of chronic asthma in a mammal.

The term “respiratory disease,” as used herein, refers to diseasesaffecting the organs that are involved in breathing, such as the nose,throat, larynx, eustachian tubes, trachea, bronchi, lungs, relatedmuscles (e.g., diaphram and intercostals), and nerves. Respiratorydiseases include, but are not limited to, asthma, adult respiratorydistress syndrome and allergic (extrinsic) asthma, non-allergic(intrinsic) asthma, acute severe asthma, chronic asthma, clinicalasthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitiveasthma, exercise-induced asthma, isocapnic hyperventilation, child-onsetasthma, adult-onset asthma, cough-variant asthma, occupational asthma,steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis,perennial allergic rhinitis, chronic obstructive pulmonary disease,including chronic bronchitis or emphysema, pulmonary hypertension,interstitial lung fibrosis and/or airway inflammation and cysticfibrosis, and hypoxia.

The term “asthma” as used herein refers to any disorder of the lungscharacterized by variations in pulmonary gas flow associated with airwayconstriction of whatever cause (intrinsic, extrinsic, or both; allergicor non-allergic). The term asthma may be used with one or moreadjectives to indicate cause.

In one aspect, presented herein is the use of a compound of Formula (Ia)or (Ib), or a pharmaceutically acceptable salt or solvate thereof, inthe treatment or prevention of chronic obstructive pulmonary disease ina mammal comprising administering to the mammal at least once aneffective amount of at least one compound of Formula (Ia) or (Ib), or apharmaceutically acceptable salt or solvate thereof. In addition,chronic obstructive pulmonary disease includes, but is not limited to,chronic bronchitis or emphysema, pulmonary hypertension, interstitiallung fibrosis and/or airway inflammation, and cystic fibrosis.

Nervous System

The nervous system is a major locus for LPA₁ expression; there it isspatially and temporally regulated throughout brain development.Oligodendrocytes, the myelinating cells in the central nervous system(CNS), express LPA₁ in mammals. In addition, Schwann cells, themyelinating cells of the peripheral nervous system, also express LPA₁,which is involved in regulating Schwann cell survival and morphology.These observations identify important functions for receptor-mediatedLPA signaling in neurogenesis, cell survival, and myelination.

Exposure of peripheral nervous system cell lines to LPA produces a rapidretraction of their processes resulting in cell rounding, which was, inpart, mediated by polymerization of the actin cytoskeleton. In oneaspect, LPA causes neuronal degeneration under pathological conditionswhen the blood-brain barrier is damaged and serum components leak intothe brain (Moolenaar, Curr. Opin. Cell Biol. 7:203-10, 1995)Immortalized CNS neuroblast cell lines from the cerebral cortex alsodisplay retraction responses to LPA exposure through Rho activation andactomyosin interactions. In one aspect, LPA is associated withpost-ischemic neural damage (J. Neurochem. 61, 340, 1993; J. Neurochem.,70:66, 1998).

In one aspect, provided is a compound of Formula (Ia) or (Ib), or apharmaceutically acceptable salt or solvate thereof, for use in thetreatment or prevention of a nervous system disorder in a mammal. Theterm “nervous system disorder,” as used herein, refers to conditionsthat alter the structure or function of the brain, spinal cord orperipheral nervous system, including but not limited to Alzheimer'sDisease, cerebral edema, cerebral ischemia, stroke, multiple sclerosis,neuropathies, Parkinson's Disease, those found after blunt or surgicaltrauma (including post-surgical cognitive dysfunction and spinal cord orbrain stem injury), as well as the neurological aspects of disorderssuch as degenerative disk disease and sciatica.

In one aspect, provided is a compound of Formula (Ia) or (Ib), or apharmaceutically acceptable salt or solvate thereof, for use in thetreatment or prevention of a CNS disorder in a mammal. CNS disordersinclude, but are not limited to, multiple sclerosis, Parkinson'sdisease, Alzheimer's disease, stroke, cerebral ischemia, retinalischemia, post-surgical cognitive dysfunction, migraine, peripheralneuropathy/neuropathic pain, spinal cord injury, cerebral edema and headinjury.

Cardiovascular Disorders

Cardiovascular phenotypes observed after targeted deletion oflysophospholipid receptors reveal important roles for lysophospholipidsignaling in the development and maturation of blood vessels, formationof atherosclerotic plaques and maintenance of heart rate (Ishii, I. etal. Annu. Rev. Biochem. 73, 321-354, 2004). Angiogenesis, the formationof new capillary networks from pre-existing vasculature, is normallyinvoked in wound healing, tissue growth and myocardial angiogenesisafter ischemic injury. Peptide growth factors (e.g. vascular endothelialgrowth factor (VEGF)) and lysophospholipids control coordinatedproliferation, migration, adhesion, differentiation and assembly ofvascular endothelial cells (VECs) and surrounding vascular smooth-musclecells (VSMCs). In one aspect, dysregulation of the processes mediatingangiogenesis leads to atherosclerosis, hypertension, tumor growth,rheumatoid arthritis and diabetic retinopathy (Osborne, N. and Stainier,D. Y. Annu. Rev. Physiol. 65, 23-43, 2003).

Downstream signaling pathways evoked by lysophospholipid receptorsinclude Rac-dependent lamellipodia formation (e.g. LPA₁) andRho-dependent stress-fiber formation (e.g. LPA₁), which is important incell migration and adhesion. Dysfunction of the vascular endothelium canshift the balance from vasodilatation to vasoconstriction and lead tohypertension and vascular remodeling, which are risk factors foratherosclerosis (Maguire, J. J. et al., Trends Pharmacol. Sci. 26,448-454, 2005).

LPA contributes to both the early phase (barrier dysfunction andmonocyte adhesion of the endothelium) and the late phase (plateletactivation and intra-arterial thrombus formation) of atherosclerosis, inaddition to its overall progression. In the early phase, LPA fromnumerous sources accumulates in lesions and activates its cognate GPCRs(LPA₁ and LPA₃) expressed on platelets (Siess, W. Biochim. Biophys. Acta1582, 204-215, 2002; Rother, E. et al. Circulation 108, 741-747, 2003).This triggers platelet shape change and aggregation, leading tointra-arterial thrombus formation and, potentially, myocardialinfarction and stroke. In support of its atherogenic activity, LPA canalso be a mitogen and motogen to VSMCs and an activator of endothelialcells and macrophages. In one aspect, mammals with cardiovasculardisease benefit from LPA receptor antagonists that prevent thrombus andneointima plaque formation.

In one aspect, a compound of Formula (Ia) or (Ib), or a pharmaceuticallyacceptable salt or solvate thereof, is used to treat or preventcardiovascular disease in mammal

The term “cardiovascular disease,” as used herein refers to diseasesaffecting the heart or blood vessels or both, including but not limitedto: arrhythmia (atrial or ventricular or both); atherosclerosis and itssequelae; angina; cardiac rhythm disturbances; myocardial ischemia;myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke;peripheral obstructive arteriopathy of a limb, an organ, or a tissue;reperfusion injury following ischemia of the brain, heart or other organor tissue; endotoxic, surgical, or traumatic shock; hypertension,valvular heart disease, heart failure, abnormal blood pressure; shock;vasoconstriction (including that associated with migraines); vascularabnormality, inflammation, insufficiency limited to a single organ ortissue.

In one aspect, provided herein are methods for preventing or treatingvasoconstriction, atherosclerosis and its sequelae myocardial ischemia,myocardial infarction, aortic aneurysm, vasculitis and stroke comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (Ia) or (Ib), or a pharmaceuticallyacceptable salt or solvate thereof, or pharmaceutical composition ormedicament which includes a compound of Formula (Ia) or (Ib), or apharmaceutically acceptable salt or solvate thereof.

In one aspect, provided herein are methods for reducing cardiacreperfusion injury following myocardial ischemia and/or endotoxic shockcomprising administering at least once to the mammal an effective amountof at least one compound of Formula (Ia) or (Ib), or a pharmaceuticallyacceptable salt or solvate thereof.

In one aspect, provided herein are methods for reducing the constrictionof blood vessels in a mammal comprising administering at least once tothe mammal an effective amount of at least one compound of Formula (Ia)or (Ib), or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, provided herein are methods for lowering or preventing anincrease in blood pressure of a mammal comprising administering at leastonce to the mammal an effective amount of at least one compound ofFormula (Ia) or (Ib), or a pharmaceutically acceptable salt or solvatethereof

Inflammation

LPA has been shown to regulate immunological responses by modulatingactivities/functions of immune cells such as T-/B-lymphocytes andmacrophages. In activated T cells, LPA activates IL-2 production/cellproliferation through LPA₁ (Gardell et al, TRENDS in Molecular MedicineVol. 12 No. 2 Feb. 2006). Expression of LPA-induced inflammatoryresponse genes is mediated by LPA₁ and LPA₃ (Biochem Biophys Res Commun.363(4):1001-8, 2007). In addition, LPA modulates the chemotaxis ofinflammatory cells (Biochem Biophys Res Commun., 1993, 15; 193(2), 497).The proliferation and cytokine-secreting activity in response to LPA ofimmune cells (J. Imuunol. 1999, 162, 2049), platelet aggregationactivity in response to LPA, acceleration of migration activity inmonocytes, activation of NF-κB in fibroblast, enhancement offibronectin-binding to the cell surface, and the like are known. Thus,LPA is associated with various inflammatory/immune diseases.

In one aspect, a compound of Formula (Ia) or (Ib), or a pharmaceuticallyacceptable salt or solvate thereof, is used to treat or preventinflammation in a mammal. In one aspect, antagonists of LPA₁ and/or LPA₃find use in the treatment or prevention of inflammatory/immune disordersin a mammal. In one aspect, the antagonist of LPA₁ is a compound ofFormula (Ia) or (Ib), or a pharmaceutically acceptable salt or solvatethereof.

Examples of inflammatory/immune disorders include psoriasis, rheumatoidarthritis, vasculitis, inflammatory bowel disease, dermatitis,osteoarthritis, asthma, inflammatory muscle disease, allergic rhinitis,vaginitis, interstitial cystitis, scleroderma, eczema, allogeneic orxenogeneic transplantation (organ, bone marrow, stem cells and othercells and tissues) graft rejection, graft-versus-host disease, lupuserythematosus, inflammatory disease, type I diabetes, pulmonaryfibrosis, deimatomyositis, Sjogren's syndrome, thyroiditis (e.g.,Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmunehemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsinghepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopicdermatitis.

Other Diseases, Disorders or Conditions

In accordance with one aspect, are methods for treating, preventing,reversing, halting or slowing the progression of LPA-dependent orLPA-mediated diseases or conditions once it becomes clinically evident,or treating the symptoms associated with or related to LPA-dependent orLPA-mediated diseases or conditions, by administering to the mammal acompound of Formula (Ia) or (Ib), or a pharmaceutically acceptable saltor solvate thereof. In certain embodiments, the subject already has aLPA-dependent or LPA-mediated disease or condition at the time ofadministration, or is at risk of developing a LPA-dependent orLPA-mediated disease or condition.

In certain aspects, the activity of LPA₁ in a mammal is directly orindirectly modulated by the administration of (at least once) atherapeutically effective amount of at least one compound of Formula(Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof.Such modulation includes, but is not limited to, reducing and/orinhibiting the activity of LPA₁. In additional aspects, the activity ofLPA in a mammal is directly or indirectly modulated, including reducingand/or inhibiting, by the administration of (at least once) atherapeutically effective amount of at least one compound of Formula(Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof.Such modulation includes, but is not limited to, reducing and/orinhibiting the amount and/or activity of a LPA receptor. In one aspect,the LPA receptor is LPA₁.

In one aspect, LPA has a contracting action on bladder smooth musclecell isolated from bladder, and promotes growth of prostate-derivedepithelial cell (J. Urology, 1999, 162, 1779-1784; J. Urology, 2000,163, 1027-1032). In another aspect, LPA contracts the urinary tract andprostate in vitro and increases intraurethral pressure in vivo (WO02/062389).

In certain aspects, are methods for preventing or treating eosinophiland/or basophil and/or dendritic cell and/or neutrophil and/or monocyteand/or T-cell recruitment comprising administering at least once to themammal an effective amount of at least one compound of Formula (Ia) or(Ib), or a pharmaceutically acceptable salt or solvate thereof.

In certain aspects, are methods for the treatment of cystitis,including, e.g., interstitial cystitis, comprising administering atleast once to the mammal a therapeutically effective amount of at leastone compound of Formula (Ia) or (Ib), or a pharmaceutically acceptablesalt or solvate thereof.

In accordance with one aspect, methods described herein include thediagnosis or determination of whether or not a patient is suffering froma LPA-dependent or LPA-mediated disease or condition by administering tothe subject a therapeutically effective amount of a compound of Formula(Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof,and determining whether or not the patient responds to the treatment.

In one aspect provided herein are compounds of Formula (Ia) or (Ib),pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs,and pharmaceutically acceptable solvates thereof, which are antagonistsof LPA₁, and are used to treat patients suffering from one or moreLPA-dependent or LPA-mediated conditions or diseases, including, but notlimited to, lung fibrosis, kidney fibrosis, liver fibrosis, scarring,asthma, rhinitis, chronic obstructive pulmonary disease, pulmonaryhypertension, interstitial lung fibrosis, arthritis, allergy, psoriasis,inflammatory bowel disease, adult respiratory distress syndrome,myocardial infarction, aneurysm, stroke, cancer, pain, proliferativedisorders and inflammatory conditions. In some embodiments,LPA-dependent conditions or diseases include those wherein an absoluteor relative excess of LPA is present and/or observed.

In any of the aforementioned aspects the LPA-dependent or LPA-mediateddiseases or conditions include, but are not limited to, organ fibrosis,asthma, allergic disorders, chronic obstructive pulmonary disease,pulmonary hypertension, lung or pleural fibrosis, peritoneal fibrosis,arthritis, allergy, cancer, cardiovascular disease, ult respiratorydistress syndrome, myocardial infarction, aneurysm, stroke, and cancer.

In one aspect, a compound of Formula (Ia) or (Ib), or a pharmaceuticallyacceptable salt or solvate thereof, is used to improve the cornealsensitivity decrease caused by corneal operations such as laser-assistedin situ keratomileusis (LASIK) or cataract operation, cornealsensitivity decrease caused by corneal degeneration, and dry eye symptomcaused thereby.

In one aspect, presented herein is the use of a compound of Formula (Ia)or (Ib), or a pharmaceutically acceptable salt or solvate thereof, inthe treatment or prevention of ocular inflammation and allergicconjunctivitis, vernal keratoconjunctivitis, and papillaryconjunctivitis in a mammal comprising administering at least once to themammal an effective amount of at least one compound of Formula (Ia) or(Ib), or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, presented herein is the use of a compound of Formula (Ia)or (Ib), or a pharmaceutically acceptable salt or solvate thereof, inthe treatment or prevention of Sjogren disease or inflammatory diseasewith dry eyes in a mammal comprising administering at least once to themammal an effective amount of at least one compound of Formula (Ia) or(Ib), or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, LPA and LPA receptors (e.g. LPA₁) are involved in thepathogenesis of osteoarthritis (Kotani et al, Hum. Mol. Genet., 2008,17, 1790-1797). In one aspect, presented herein is the use of a compoundof Formula (Ia) or (Ib), or a pharmaceutically acceptable salt orsolvate thereof, in the treatment or prevention of osteoarthritis in amammal comprising administering at least once to the mammal an effectiveamount of at least one compound of Formula (Ia) or (Ib), or apharmaceutically acceptable salt or solvate thereof.

In one aspect, LPA receptors (e.g. LPA₁, LPA₃) contribute to thepathogenesis of rheumatoid arthritis (Zhao et al, Mol. Pharmacol., 2008,73(2), 587-600). In one aspect, presented herein is the use of acompound of Formula (Ia) or (Ib), or a pharmaceutically acceptable saltor solvate thereof, in the treatment or prevention of rheumatoidarthritis in a mammal comprising administering at least once to themammal an effective amount of at least one compound of Formula (Ia) or(Ib), or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, LPA receptors (e.g. LPA₁) contribute to adipogenesis.(Simon et al, J. Biol. Chem., 2005, vol. 280, no. 15, p. 14656). In oneaspect, presented herein is the use of a compound of Formula (Ia) or(Ib), or a pharmaceutically acceptable salt or solvate thereof, in thepromotion of adipose tissue formation in a mammal comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (Ia) or (Ib), or a pharmaceuticallyacceptable salt or solvate thereof.

a. In Vitro Assays

The effectiveness of compounds of the present invention as LPA₁inhibitors can be determined in an LPA₁ functional antagonist assay asfollows:

Chinese hamster ovary cells overexpressing human LPA₁ were platedovernight (15,000 cells/well) in poly-D-lysine coated 384-wellmicroplates (Greiner bio-one, Cat #781946) in DMEM/F12 medium (Gibco,Cat #11039). Following overnight culture, cells were loaded with calciumindicator dye (AAT Bioquest Inc, Cat #34601) for 30 minutes at 37° C.The cells were then equilibrated to room temperature for 30 minutesbefore the assay. Test compounds solubilized in DMSO were transferred to384 well non-binding surface plates (Corning, Cat #3575) using theLabcyte Echo acoustic dispense and diluted with assay buffer [1X HBSSwith calcium/magnesium (Gibco Cat #14025-092), 20 mM HEPES (Gibco Cat#15630-080) and 0.1% fatty acid free BSA (Sigma Cat # A9205)] to a finalconcentration of 0.5% DMSO. Diluted compounds were added to the cells byFDSS6000 (Hamamatsu) at final concentrations ranging from 0.08 nM to 5μM. and were then incubated for 20 min at room temperature at which timeLPA (Avanti Polar Lipids Cat #857130C) was added at final concentrationsof 10 nM to stimulate the cells. The compound IC₅₀ value was defined asthe concentration of test compound which inhibited 50% of the calciumflux induced by LPA alone. IC₅₀ values were determined by fitting datato a 4-parameter logistic equation (GraphPad Prism, San Diego Calif.).

b. In Vivo Assays

LPA Challenge with plasma histamine evaluation.

Compound is dosed orally p.o. 2 hours to CD-1 female mice prior to theLPA challenge. The mice are then dosed via tail vein (IV) with 0.15 mLof LPA in 0.1% BSA/PBS (2 μg/μL). Exactly 2 minutes following the LPAchallenge, the mice are euthanized by decapitation and the trunk bloodis collected. These samples are collectively centrifuged and individual75 μL samples are frozen at −20° C. until the time of the histamineassay.

The plasma histamine analysis was run by standard EIA (EnzymeImmunoassay) methods. Plasma samples were thawed and diluted 1:30 in0.1% BSA in PBS. The EIA protocol for histamine analysis as outlined bythe manufacturer was followed (Histamine EIA, Oxford BiomedicalResearch, EA #31).

The LPA used in the assay is formulated as follows: LPA(1-oleoyl-2-hydroxy-sn-glycero-3-phosphate (sodium salt), 857130P,Avanti Polar Lipids) is prepared in 0.1% BSA/PBS for total concentrationof 2 μg/μL. 13 mg of LPA is weighed and 6.5 mL 0.1% BSA added, vortexedand sonicated for ˜1 hour until a clear solution is achieved.

V. Pharmaceutical Compositions, Formulations and Combinations

In some embodiments, provided is a pharmaceutical composition comprisinga therapeutically effective amount of a compound of Formula (Ia) or(Ib), or a pharmaceutically acceptable salt or solvate thereof. In someembodiments, the pharmaceutical composition also contains at least onepharmaceutically acceptable inactive ingredient.

In some embodiments, provided is a pharmaceutical composition comprisinga therapeutically effective amount of a compound of Formula (Ia) or(Ib), or a pharmaceutically acceptable salt or solvate thereof, and atleast one pharmaceutically acceptable inactive ingredient. In oneaspect, the pharmaceutical composition is formulated for intravenousinjection, subcutaneous injection, oral administration, inhalation,nasal administration, topical administration, ophthalmic administrationor otic administration. In some embodiments, the pharmaceuticalcomposition is a tablet, a pill, a capsule, a liquid, an inhalant, anasal spray solution, a suppository, a suspension, a gel, a colloid, adispersion, a suspension, a solution, an emulsion, an ointment, alotion, an eye drop or an ear drop.

In some embodiments, the pharmaceutical composition further comprisesone or more additional therapeutically active agents selected from:corticosteroids (e.g., dexamethasone or fluticasone), immunosuppresants(e.g., tacrolimus & pimecrolimus), analgesics, anti-cancer agent,anti-inflammatories, chemokine receptor antagonists, bronchodilators,leukotriene receptor antagonists (e.g., montelukast or zafirlukast),leukotriene formation inhibitors, monoacylglycerol kinase inhibitors,phospholipase A₁ inhibitors, phospholipase A₂ inhibitors, andlysophospholipase D (lysoPLD) inhibitors, autotaxin inhibitors,decongestants, antihistamines (e.g., loratidine), mucolytics,anticholinergics, antitussives, expectorants, anti-infectives (e.g.,fusidic acid, particularly for treatment of atopic dermatitis),anti-fungals (e.g., clotriazole, particularly for atopic demiatitis),anti-IgE antibody therapies (e.g., omalizumab), β-2 adrenergic agonists(e.g., albuterol or salmeterol), other PGD2 antagonists acting at otherreceptors such as DP antagonists, PDE4 inhibitors (e.g., cilomilast),drugs that modulate cytokine production, e.g., TACE inhibitors, drugsthat modulate activity of Th2 cytokines IL-4 & IL-5 (e.g., blockingmonoclonal antibodies & soluble receptors), PPARγ agonists (e.g.,rosiglitazone and pioglitazone), 5-lipoxygenase inhibitors (e.g.,zileuton).

In some embodiments, the pharmaceutical composition further comprisesone or more additional anti-fibrotic agents selected from pirfenidone,nintedanib, thalidomide, carlumab, FG-3019, fresolimumab, interferonalpha, lecithinized superoxide dismutase, simtuzumab, tanzisertib,tralokinumab, hu3G9, AM-152, IFN-gamma-1b, IW-001, PRM-151, PXS-25,pentoxifylline/N-acetyl-cysteine, pentoxifylline/vitamin E, salbutamolsulfate, [Sar9,Met(O2)11]-Substance P, pentoxifylline, mercaptaminebitartrate, obeticholic acid, aramchol, GFT-505, eicosapentaenoic acidethyl ester, metformin, metreleptin, muromonab-CD3, oltipraz, IMM-124-E,MK-4074, PX-102, RO-5093151. In some embodiments, provided is a methodcomprising administering a compound of Formula (Ia) or (Ib), or apharmaceutically acceptable salt or solvate thereof, to a human with aLPA-dependent or LPA-mediated disease or condition. In some embodiments,the human is already being administered one or more additionaltherapeutically active agents other than a compound of Formula (Ia) or(Ib), or a pharmaceutically acceptable salt or solvate thereof. In someembodiments, the method further comprises administering one or moreadditional therapeutically active agents other than a compound ofFormula (Ia) or (Ib), or a pharmaceutically acceptable salt or solvatethereof.

In some embodiments, the one or more additional therapeutically activeagents other than a compound of Formula (Ia) or (Ib), or apharmaceutically acceptable salt or solvate thereof, are selected from:corticosteroids (e.g, dexamethasone or fluticasone), immunosuppresants(e.g., tacrolimus & pimecrolimus), analgesics, anti-cancer agent,anti-inflammatories, chemokine receptor antagonists, bronchodilators,leukotriene receptor antagonists (e.g., montelukast or zafirlukast),leukotriene formation inhibitors, monoacylglycerol kinase inhibitors,phospholipase A₁ inhibitors, phospholipase A₂ inhibitors, andlysophospholipase D (lysoPLD) inhibitors, autotaxin inhibitors,decongestants, antihistamines (e.g., loratidine), mucolytics,anticholinergics, antitussives, expectorants, anti-infectives (e.g.,fusidic acid, particularly for treatment of atopic dermatitis),anti-fungals (e.g., clotriazole, particularly for atopic dermatitis),anti-IgE antibody therapies (e.g., omalizumab), β-2 adrenergic agonists(e.g., albuterol or salmeterol), other PGD2 antagonists acting at otherreceptors such as DP antagonists, PDE4 inhibitors (e.g., cilomilast),drugs that modulate cytokine production, e.g. TACE inhibitors, drugsthat modulate activity of Th2 cytokines IL-4 & IL-5 (e.g., blockingmonoclonal antibodies & soluble receptors), PPARγ agonists (e.g.,rosiglitazone and pioglitazone), 5-lipoxygenase inhibitors (e.g.,zileuton).

In some embodiments, the one or more additional therapeutically activeagents other than a compound of Formula (Ia) or (Ib), or apharmaceutically acceptable salt or solvate thereof, are otheranti-fibrotic agents selected from pirfenidone, nintedanib, thalidomide,carlumab, FG-3019, fresolimumab, interferon alpha, lecithinizedsuperoxide dismutase, simtuzumab, tanzisertib, tralokinumab, hu3G9,AM-152, IFN-gamma-1b, IW-001, PRM-151, PXS-25,pentoxifylline/N-acetyl-cysteine, pentoxifylline/vitamin E, salbutamolsulfate, [Sar9,Met(O2)11]-Substance P, pentoxifylline, mercaptaminebitartrate, obeticholic acid, aramchol, GFT-505, eicosapentyl ethylester, metformin, metreleptin, muromonab-CD3, oltipraz, IMM-124-E,MK-4074, PX-102, RO-5093151.

In some embodiments, the one or more additional therapeutically activeagents other than a compound of Formula (Ia) or (Ib), or apharmaceutically acceptable salt or solvate thereof, are selected fromACE inhibitors, ramipril, All antagonists, irbesartan, anti-arrythmics,dronedarone, PPARα activators, PPARγ activators, pioglitazone,rosiglitazone, prostanoids, endothelin receptor antagonists, elastaseinhibitors, calcium antagonists, beta blockers, diuretics, aldosteronereceptor antagonists, eplerenone, renin inhibitors, rho kinaseinhibitors, soluble guanylate cyclase (sGC) activators, sGC sensitizers,PDE inhibitors, PDE5 inhibitors, NO donors, digitalis drugs, ACE/NEPinhibitors, statins, bile acid reuptake inhibitors, PDGF antagonists,vasopressin antagonists, aquaretics, NHE1 inhibitors, Factor Xaantagonists, Factor XIIIa antagonists, anticoagulants, anti-thrombotics,platelet inhibitors, profibroltics, thrombin-activatable fibrinolysisinhibitors (TAFI), PAI-1 inhibitors, coumarins, heparins, thromboxaneantagonists, serotonin antagonists, COX inhibitors, aspirin, therapeuticantibodies, GPIIb/IIIa antagonists, ER antagonists, SERMs, tyrosinekinase inhibitors, RAF kinase inhibitors, p38 MAPK inhibitors,pirfenidone, multi-kinase inhibitors, nintedanib, sorafenib.

In some embodiments, the one or more additional therapeutically activeagents other than a compound of Formula (Ia) or (Ib), or apharmaceutically acceptable salt or solvate thereof, are selected fromGremlin-1 mAb, PA1-1 mAb, Promedior (PRM-151; recombinant humanPentraxin-2); FGF21, TGFβ antagonists, αvβ6 & αvβ pan-antagonists; FAKinhibitors, TG2 inhibitors, LOXL2 inhibitors, NOX4 inhibitors, MGAT2inhibitors, GPR120 agonists.

Pharmaceutical formulations described herein are administrable to asubject in a variety of ways by multiple administration routes,including but not limited to, oral, parenteral (e.g., intravenous,subcutaneous, intramuscular), intranasal, buccal, topical or transdermaladministration routes. The pharmaceutical formulations described hereininclude, but are not limited to, aqueous liquid dispersions,self-emulsifying dispersions, solid solutions, liposomal dispersions,aerosols, solid dosage forms, powders, immediate release formulations,controlled release formulations, fast melt formulations, tablets,capsules, pills, delayed release formulations, extended releaseformulations, pulsatile release formulations, multiparticulateformulations, and mixed immediate and controlled release formulations.

In some embodiments, the compound of Formula (Ia) or (Ib), or apharmaceutically acceptable salt or solvate thereof, is administeredorally.

In some embodiments, the compound of Formula (Ia) or (Ib), or apharmaceutically acceptable salt or solvate thereof, is administeredtopically. In such embodiments, the compound of Formula (Ia) or (Ib), ora pharmaceutically acceptable salt or solvate thereof, is formulatedinto a variety of topically administrable compositions, such assolutions, suspensions, lotions, gels, pastes, shampoos, scrubs, rubs,smears, medicated sticks, medicated bandages, balms, creams orointments. Such pharmaceutical compounds can contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives. Inone aspect, the compound of Formula (Ia) or (Ib), or a pharmaceuticallyacceptable salt or solvate thereof, is administered topically to theskin.

In another aspect, the compound of Formula (Ia) or (Ib), or apharmaceutically acceptable salt or solvate thereof, is administered byinhalation. In one embodiment, the compound of Formula (Ia) or (Ib), ora pharmaceutically acceptable salt or solvate thereof, is administeredby inhalation that directly targets the pulmonary system.

In another aspect, the compound of Formula (Ia) or (Ib), or apharmaceutically acceptable salt or solvate thereof, is formulated forintranasal administration. Such formulations include nasal sprays, nasalmists, and the like.

In another aspect, the compound of Formula (Ia) or (Ib), or apharmaceutically acceptable salt or solvate thereof, is formulated aseye drops.

In another aspect is the use of a compound of Formula (Ia) or (Ib), or apharmaceutically acceptable salt or solvate thereof, in the manufactureof a medicament for treating a disease, disorder or conditions in whichthe activity of at least one LPA receptor contributes to the pathologyand/or symptoms of the disease or condition. In one embodiment of thisaspect, the LPA is selected from LPA₁, LPA₂, LPA₃, LPA₄, LPA₅ and LPA₆.In one aspect, the LPA receptor is LPA₁. In one aspect, the disease orcondition is any of the diseases or conditions specified herein.

In any of the aforementioned aspects are further embodiments in which:(a) the effective amount of the compound of Formula (Ia) or (Ib), or apharmaceutically acceptable salt or solvate thereof, is systemicallyadministered to the mammal; and/or (b) the effective amount of thecompound is administered orally to the mammal; and/or (c) the effectiveamount of the compound is intravenously administered to the mammal;and/or (d) the effective amount of the compound is administered byinhalation; and/or (e) the effective amount of the compound isadministered by nasal administration; or and/or (f) the effective amountof the compound is administered by injection to the mammal; and/or (g)the effective amount of the compound is administered topically to themammal; and/or (h) the effective amount of the compound is administeredby ophthalmic administration; and/or (i) the effective amount of thecompound is administered rectally to the mammal; and/or (j) theeffective amount is administered non-systemically or locally to themammal

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce; (ii) the compound is administered to the mammal multiple timesover the span of one day; (iii) continually; or (iv) continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours; (iv) the compound isadministered to the mammal every 12 hours; (v) the compound isadministered to the mammal every 24 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound is temporarily suspended or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

Also provided is a method of inhibiting the physiological activity ofLPA in a mammal comprising administering a therapeutically effectiveamount of a compound of Formula (Ia) or (Ib) or a pharmaceuticallyacceptable salt or solvate thereof to the mammal in need thereof.

In one aspect, provided is a medicament for treating a LPA-dependent orLPA-mediated disease or condition in a mammal comprising atherapeutically effective amount of a compound of Formula (Ia) or (Ib),or a pharmaceutically acceptable salt or solvate thereof.

In some cases disclosed herein is the use of a compound of Formula (Ia)or (Ib), or a pharmaceutically acceptable salt or solvate thereof, inthe manufacture of a medicament for the treatment of a LPA-dependent orLPA-mediated disease or condition.

In some cases disclosed herein is the use of a compound of Formula (Ia)or (Ib), or a pharmaceutically acceptable salt or solvate thereof, inthe treatment or prevention of a LPA-dependent or LPA-mediated diseaseor condition.

In one aspect, is a method for treating or preventing a LPA-dependent orLPA-mediated disease or condition in a mammal comprising administering atherapeutically effective amount of a compound of Formula (Ia) or (Ib),or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, LPA-dependent or LPA-mediated diseases or conditionsinclude, but are not limited to, fibrosis of organs or tissues,scarring, liver diseases, dermatological conditions, cancer,cardiovascular disease, respiratory diseases or conditions, inflammatorydisease, gastrointestinal tract disease, renal disease, urinarytract-associated disease, inflammatory disease of lower urinary tract,dysuria, frequent urination, pancreas disease, arterial obstruction,cerebral infarction, cerebral hemorrhage, pain, peripheral neuropathy,and fibromyalgia.

In one aspect, the LPA-dependent or LPA-mediated disease or condition isa respiratory disease or condition. In some embodiments, the respiratorydisease or condition is asthma, chronic obstructive pulmonary disease(COPD), pulmonary fibrosis, pulmonary arterial hypertension or acuterespiratory distress syndrome.

In some embodiments, the LPA-dependent or LPA-mediated disease orcondition is selected from idiopathic pulmonary fibrosis; other diffuseparenchymal lung diseases of different etiologies including iatrogenicdrug-induced fibrosis, occupational and/or environmental inducedfibrosis, granulomatous diseases (sarcoidosis, hypersensitivitypneumonia), collagen vascular disease, alveolar proteinosis, langerhanscell granulomatosis, lymphangioleiomyomatosis, inherited diseases(Heiinansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis,metabolic storage disorders, familial interstitial lung disease);radiation induced fibrosis; chronic obstructive pulmonary disease(COPD); scleroderma; bleomycin induced pulmonary fibrosis; chronicasthma; silicosis; asbestos induced pulmonary fibrosis; acuterespiratory distress syndrome (ARDS); kidney fibrosis;tubulointerstitium fibrosis; glomerular nephritis; focal segmentalglomerular sclerosis; IgA nephropathy; hypertension; Alport; gutfibrosis; liver fibrosis; cirrhosis; alcohol induced liver fibrosis;toxic/drug induced liver fibrosis; hemochromatosis; nonalcoholicsteatohepatitis (NASH); biliary duct injury; primary biliary cirrhosis;infection induced liver fibrosis; viral induced liver fibrosis; andautoimmune hepatitis; corneal scarring; hypertrophic scarring; Duputrendisease, keloids, cutaneous fibrosis; cutaneous scleroderma; spinal cordinjury/fibrosis; myelofibrosis; vascular restenosis; atherosclerosis;arteriosclerosis; Wegener's granulomatosis; Peyronie's disease, chroniclymphocytic leukemia, tumor metastasis, transplant organ rejection,endometriosis, neonatal respiratory distress syndrome and neuropathicpain.

In one aspect, the LPA-dependent or LPA-mediated disease or condition isdescribed herein.

In one aspect, provided is a method for the treatment or prevention oforgan fibrosis in a mammal comprising administering a therapeuticallyeffective amount of a compound of Formula (Ia) or (Ib) or apharmaceutically acceptable salt or solvate thereof to a mammal in needthereof.

In one aspect, the organ fibrosis comprises lung fibrosis, renalfibrosis, or hepatic fibrosis.

In one aspect, provided is a method of improving lung function in amammal comprising administering a therapeutically effective amount of acompound of Formula (Ia) or (Ib), or a pharmaceutically acceptable saltor solvate thereof to the mammal in need thereof. In one aspect, themammal has been diagnosed as having lung fibrosis.

In one aspect, compounds disclosed herein are used to treat idiopathicpulmonary fibrosis (usual interstitial pneumonia) in a mammal.

In some embodiments, compounds disclosed herein are used to treatdiffuse parenchymal interstitial lung diseases in mammal: iatrogenicdrug induced, occupational/environmental (Farmer lung), granulomatousdiseases (sarcoidosis, hypersensitivity pneumonia), collagen vasculardisease (scleroderma and others), alveolar proteinosis, langerhans cellgranulonmatosis, lymphangioleiomyomatosis, Hermansky-Pudlak Syndrome,Tuberous sclerosis, neurofibromatosis, metabolic storage disorders,familial interstitial lung disease.

In some embodiments, compounds disclosed herein are used to treatpost-transplant fibrosis associated with chronic rejection in a mammal:Bronchiolitis obliterans for lung transplant.

In some embodiments, compounds disclosed herein are used to treatcutaneous fibrosis in a mammal: cutaneous scleroderma, Dupuytrendisease, keloids.

In one aspect, compounds disclosed herein are used to treat hepaticfibrosis with or without cirrhosis in a mammal: toxic/drug induced(hemochromatosis), alcoholic liver disease, viral hepatitis (hepatitis Bvirus, hepatitis C virus, HCV), nonalcoholic liver disease (NAFLD,NASH), metabolic and auto-immune disease.

In one aspect, compounds disclosed herein are used to treat renalfibrosis in a mammal: tubulointerstitium fibrosis, glomerular sclerosis.

In any of the aforementioned aspects involving the treatment of LPAdependent diseases or conditions are further embodiments comprisingadministering at least one additional agent in addition to theadministration of a compound having the structure of Formula (Ia) or(Ib), or a pharmaceutically acceptable salt or solvate thereof. Invarious embodiments, each agent is administered in any order, includingsimultaneously.

In any of the embodiments disclosed herein, the mammal is a human

In some embodiments, compounds provided herein are administered to ahuman.

In some embodiments, compounds provided herein are orally administered.

In some embodiments, compounds provided herein are used as antagonistsof at least one LPA receptor. In some embodiments, compounds providedherein are used for inhibiting the activity of at least one LPA receptoror for the treatment of a disease or condition that would benefit frominhibition of the activity of at least one LPA receptor. In one aspect,the LPA receptor is LPA₁.

In other embodiments, compounds provided herein are used for theformulation of a medicament for the inhibition of LPA₁ activity.

Articles of manufacture, which include packaging material, a compound ofFormula (Ia) or (Ib), or a pharmaceutically acceptable salt or solvatethereof, within the packaging material, and a label that indicates thatthe compound or composition, or pharmaceutically acceptable salt,tautomers, pharmaceutically acceptable N-oxide, pharmaceutically activemetabolite, pharmaceutically acceptable prodrug, or pharmaceuticallyacceptable solvate thereof, is used for inhibiting the activity of atleast one LPA receptor, or for the treatment, prevention or ameliorationof one or more symptoms of a disease or condition that would benefitfrom inhibition of the activity of at least one LPA receptor, areprovided.

VI. General Synthesis Including Schemes

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene et al., (Protective Groups in Organic Synthesis,Fourth Edition, Wiley-Interscience (2006)).

The compounds of Formula (Ia) or (Ib) may be prepared by the exemplaryprocesses described in the following schemes and working examples, aswell as relevant published literature procedures that are used by oneskilled in the art. Exemplary reagents and procedures for thesereactions appear herein after and in the working examples. Protectionand deprotection in the processes below may be carried out by proceduresgenerally known in the art (see, for example, Wuts, P. G. M., Greene'sProtective Groups in Organic Synthesis, 5th Edition, Wiley (2014)).General methods of organic synthesis and functional grouptransformations are found in: Trost, B. M. et al., Eds., ComprehensiveOrganic Synthesis: Selectivity, Strategy & Efficiency in Modern OrganicChemistry, Pergamon Press, New York, N.Y. (1991); Smith, M. B. et al.,March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure. 7th Edition, Wiley, New York, N.Y. (2013); Katritzky, A. R.et al., Eds., Comprehensive Organic Functional Group Transformations II,2nd Edition, Elsevier Science Inc., Tarrytown, N.Y. (2004); Larock, R.C., Comprehensive Organic Transformations, 2^(nd) Edition, Wiley-VCH,New York, N.Y. (1999), and references therein.

Scheme 1 describes the synthesis of isoxazole-azinearyl(heteroaryl)cyclohexyl acids 15. A 4-halo (preferably bromo) phenylor azine (e.g. pyridine) benzoic acid 1 is converted to thecorresponding acid chloride (e.g. with SOCl₂ or oxalylchloride/catalytic DMF). This acid chloride intermediate is reacted withan appropriate β-enamino-ester 2 followed by condensation withhydroxylamine to furnish the corresponding 5-halo(hetero)aryl-isoxazole4-carboxylate ester 3. Deprotection of the ester 3 followed by reductionof the resulting acid (e.g. directly with diborane or by a 2-stepprocedure by reacting the acid with an alkyl chloroformate followed byreduction with e.g. NaBH₄ at low temperature) and protection of theresulting alcohol provides the 5-halo(hetero)aryl-isoxazole protectedalcohol 4. Reaction of the haloaryl- or haloheteroaryl-isoxazoles 4 withpinacol diboronate in the presence of an appropriate palladium catalyst(e.g. Ishiyama, T. et al, J. Org. Chem. 1995, 60, 7508-7510) providesthe corresponding pinacol boronate 5, which is then oxidized withhydrogen peroxide to give the corresponding phenol or hydroxyheteroarene6 (Fukumoto, S. et al, WO 2012137982). Reaction ofphenol/hydroxyheteroarene 6 with a 3-hydroxy cyclohexyl ester 7 underMitsunobu reaction conditions (Kumara Swamy, K. C., Chem. Rev., 2009,109, 2551-2651) furnishes the corresponding isoxazole cycloalkyl etherester 8. Deprotection of the hydoxymethylisoxazole 8 provides thecyclohexyl ester isoxazole alcohol 9. Isoxazole alcohol 9 is thenreacted with PBr₃ (or another mild brominating agent such as CBr₄/Ph₃P)to give the corresponding bromide 10. Displacement of isoxazole bromide10 with NaN₃ (or other azide equivalent reagents) gives isoxazole azide11 which undergoes reduction (e.g. Staudinger reduction with Ph₃P/water)to afford isoxazole amine 12. Isoxazole amine 12 is then reacted withhalo-pyridine/pyrimidine 13 in the presence of an appropriate base(nucleophilic aromatic substitution) or via transition-metal (e.g.Pd)-catalyzed amination to give the isoxazole amino-azine 14.Deprotection of the isoxazole amino-azine cylohexyl ester 14 providesthe desired isoxazole amino-azine cylohexyl acids 15.

Scheme 2 describes an alternative synthetic route to theamino-aryl/heteroaryl isoxazole-aryloxy cyclohexyl acids 15. Reaction ofthe amino-azine 16 with the bromide 10 either in the presence of base(e.g. NaH, etc.,) or under transition metal-catalysis conditions (e.g.Pd-ligand-mediated) affords the amino-azine methyl isoxazole-aryloxycyclohexyl ester 14. Subsequent ester deprotection of cyclohexyl ester14 provides the desired amino-azine isoxazole-aryl/heteroaryl-oxycyclohexyl acids 15.

Scheme 3 describes a synthetic route to the isoxazole-triazine aryloxycyclohexyl acids 20 and 22. Reaction of a dihalotriazine 17 with theisoxazole-amine 12 in the presence of base affords thehalotriazinyl-isoxazole-aryloxy cyclohexyl ester 18. Subsequentdehalogenation of the halotriazine isoxazole 18 provides theisoxazole-triazine 19. Deprotection of isoxazole-triazine cyclohexylester 19 provides the isoxazole-triazine cyclohexyl acids 20.Alternatively, displacement of halogen of halotriazine-isoxazole 18 withan alcohol (R⁴OH) in the presence of base gives thealkoxytriazine-isoxazole 21. Deprotection of isoxazole-alkoxytriazinecyclohexyl ester 21 provides the isoxazole-triazine cyclohexyl acids 22.

Scheme 4 describes an alternative synthesis of isoxazole-azinearyloxy-cyclohexyl acids 15. The halo-isoxazole 4 is deprotected to givethe isoxazole alcohol, which is then converted to the correspondingisoxazole bromide 23 (with a brominating agent such as PBr₃ orCBr₄/Ph₃P), and subsequently to the isoxazole amine 24 (via a 2-stepsequence as in Scheme 1 with NaN₃ displacement of the bromide, followedby a Staudinger reduction of the azide product [Ph₃P/H₂O]). Idsoxazoleamine 42 is then subjected to either a base-mediated reaction or atransition-metal-catalyzed cross-coupling reaction (e.g.palladium-mediated) with a halo-azine 13 to furnish the isoxazoleamino-azine 25. Conversion of the bromo-aryl/heteroaryl isoxazole 25 tothe corresponding hydroxy-aryl/heteroaryl isoxazole 26 is achieved viathe corresponding boronate using the 2 step sequence[B(pin)₂/Pd-catalysis followed by treatment with H₂O₂] described inScheme 1. Hydroxyaryl/hydroxyheteroaryl isoxazole 26 is then subjectedto a Mitsunobu reaction with hydroxy-cyclohexyl ester 7 to give theisoxazole-azine-cyclohexyl ester 14 followed by deprotection to providethe desired isoxazole-azine cyclohexyl acids 15 (as described in Scheme1).

Scheme 5 describes the synthesis of isoxazole-ethyl-azine cyclohexylacids 33. The isoxazole methanol intermediate 9 is oxidized to thecorresponding aldehyde (e.g. Dess-Martin periodinane or Swernoxidation), which is then subjected to an olefination reaction (e.g.Wittig or Peterson olefination reaction) which provides the isoxazoleterminal olefin 27. Hydroboration of olefin 27 at the terminal carbon(e.g. with 9-BBN), followed by oxidative workup, provides thecorresponding isoxazole ethyl alcohol 28. Isoxazole ethyl alcohol 28 isthen reacted with PBr₃ (or another mild brominating agent such asCBr₄/Ph₃P) to give the corresponding bromide 29. Displacement of bromide29 with NaN₃ (or other azide equivalent reagents) gives isoxazole azide30 which undergoes reduction (e.g. Staudinger reduction with Ph₃P/water)to afford isoxazole amine 31. Isoxazole amine 31 is then reacted withhalo-azine 13 in the presence of an appropriate base or via transitionmetal (e.g. Pd)-catalyzed amination to give the isoxazole amino-azine32, which then undergoes ester deprotection to give the desiredisoxazole-ethyl-amino-azine aryloxy cyclohexyl acids 33.

Scheme 6 describes the synthesis of isoxazole amino-azine acids 38.Cyclohexyl ether isoxazole-alcohol 10 undergoes oxidation to theisoxazole carboxylic acid 34 (e.g. directly to the acid with pyridiniumdichromate or via a 2-step procedure via the aldehyde [Swern oxidationor Dess-Martin periodinane followed by NaClO₂ oxidation to the acid,e.g. Lindgren, B. O., Acta Chem. Scand. 1973, 27, 888]). Curtiusrearrangement of isxoazole acid 34 in the presence of t-butanol providesthe isoxazole NH-Boc-carbamate 35. Deprotection of the isoxazole NH-Boccarbamate 35 under acidic conditions provides the isoxazole amine 36.The isoxazole-amine 36 then undergoes a transition metal-catalyzedcross-coupling reaction with a halo-azine 13 to give the isoxazoleamino-azine cyclohexyl ester 37, which then undergoes ester deprotectionto give the desired isoxazole-aminoazine-aryloxy cyclohexyl acids 38.

Scheme 7 describes an alternative synthetic route to isoxazole-azinecyclohexyl acids 15. Oxidation of the cyclohexyl ester isoxazole alcohol9 (via either Dess-Martin periodinane or Swern oxidation) provides theisoxazole aldehyde 38 Imine formation of isoxazole aldehyde 38 with anappropriately substituted amino-azine 39 (e.g. catalyzed by a Lewis acidsuch as Ti(OiPr)₃Cl) followed by reductive amination (e.g. withNaBH(OAc)₃, ref. Abdel-Magid, A. F., et. al., J. Org. Chem. 1996, 61,3849-3862 or with NaBH₃CN) provides the corresponding isoxazoleamino-azine cyclohexyl ester. Acid deprotection of this isoxazole-azinecyclohexyl ester provides the aryl/heteroaryl-isoxazole-azine cyclohexylacids 15.

VII. EXAMPLES

The following Examples are offered as illustrative, as a partial scopeand particular embodiments of the invention and are not meant to belimiting of the scope of the invention. Abbreviations and chemicalsymbols have their usual and customary meanings unless otherwiseindicated. Unless otherwise indicated, the compounds described hereinhave been prepared, isolated and characterized using the schemes andother methods disclosed herein or may be prepared using the same.

As appropriate, reactions were conducted under an atmosphere of drynitrogen (or argon). For anhydrous reactions, DRISOLV® solvents from EMwere employed. For other reactions, reagent grade or HPLC grade solventswere utilized. Unless otherwise stated, all commercially obtainedreagents were used as received.

Microwave reactions were carried out using a 400 W Biotage Initiatorinstrument in microwave reaction vessels (0.2-0.5 mL; 0.5-2 mL; 2-5 mL;10-20 mL) under microwave (2.5 GHz) irradiation.

HPLC/MS and Preparatory/Analytical HPLC Methods Employed inCharacterization or Purification of Examples

NMR (nuclear magnetic resonance) spectra were typically obtained onBruker or JEOL 400 MHz and 500 MHz instruments in the indicatedsolvents. All chemical shifts are reported in ppm from tetramethylsilanewith the solvent resonance as the internal standard. ¹HNMR spectral dataare typically reported as follows: chemical shift, multiplicity(s=singlet, br s=broad singlet, d=doublet, dd=doublet of doublets,t=triplet, q=quartet, sep=septet, m=multiplet, app=apparent), couplingconstants (Hz), and integration.

In the examples where ¹H NMR spectra were collected in d₆-DMSO, awater-suppression sequence is often utilized. This sequence effectivelysuppresses the water signal and any proton peaks in the same regionusually between 3.30-3.65 ppm which will affect the overall protonintegration.

The term HPLC refers to a Shimadzu high performance liquidchromatography instrument with one of following methods:

HPLC-1: Sunfire C18 column (4.6×150 mm) 3.5 μm, gradient from 10 to 100%B:A for 12 min, then 3 mM hold at 100% B.

Mobile phase A: 0.05% TFA in water:CH₃CN (95:5)

Mobile phase B: 0.05% TFA in CH₃CN:water (95:5)

TFA Buffer pH=2.5; Flow rate: 1 mL/min; Wavelength: 254 nm, 220 nm.

HPLC-2: XBridge Phenyl (4.6×150 mm) 3.5 μm, gradient from 10 to 100% B:Afor 12 min, then 3 min hold at 100% B.

Mobile phase A: 0.05% TFA in water:CH₃CN (95:5)

Mobile phase B: 0.05% TFA in CH₃CN:water (95:5)

TFA Buffer pH=2.5; Flow rate: 1 mL/min; Wavelength: 254 nm, 220 nm.

HPLC-3: Chiralpak AD-H, 4.6×250 mm, 5 μm.

Mobile Phase: 30% EtOH-heptane (1:1)/70% CO₂

Flow rate=40 mL/min, 100 Bar, 35° C.; Wavelength: 220 nm

HPLC-4: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles;

Mobile Phase A: 5:95 CH₃CN:water with 10 mM NH₄OAc;

Mobile Phase B: 95:5 CH₃CN:water with 10 mM NH₄OAc;

Temperature: 50° C.; Gradient: 0-100% B over 3 min, then a 0.75-min holdat 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.

HPLC-5: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles;

Mobile Phase A: 5:95 CH₃CN:water with 0.1% TFA;

Mobile Phase B: 95:5 CH₃CN:water with 0.1% TFA;

Temperature: 50° C.; Gradient: 0-100% B over 3 min, then a 0.75-min holdat 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.

These additional HPLC and LC-MS methods were also utilized:

Method C: SUNFIRE C18 (4.6×150) mm, 3.5 micron column; Flow rate 1mL/min;

Mobile Phase A: 0.05% TFA in 95% Water/5% ACN; Mobile Phase B: 0.05% TFAin 5% Water/95% ACN; 10% B to 100% B over 25 min, then hold for 5 min at100% B;

Detection: UV at 254 and 220 nm.

Method D: X-Bridge Phenyl (4.6×150) mm, 3.5 micron column; flow rate 1mL/min;

Mobile Phase A: 0.05% TFA in 95% Water/5% ACN; Mobile Phase B: 0.05% TFAin 5% Water/95% ACN; 10% B to 100% B over 25 min, then hold for 5 min at100% B;

Detection: UV at 254 and 220 nm.

Method E: KINETIX XB-C18, (3×75) mm, 2.6 micron column; Flow rate: 1mL/min;

Mobile Phase A: 10 mM HCO₂NH₄ in 98% Water/2% ACN; Mobile Phase B: 10 mMHCO₂NH₄ in 2% Water/98% ACN; 20% B to 100% B over 4 min, then hold 0.5min at 100% B with flow rate 1.5 mL/min; Detection: UV at 220 nm.

Method F: KINETIX XB-C18, (3×75) mm, 2.6 micron column; Flow rate: 1mL/min;

Mobile Phase A: 0.1% HCOOH in 98% Water/2% ACN; Mobile Phase B: 0.1%HCOOH in 2% Water/98% ACN; 20% B to 100% B over 4 min., then hold 0.5min at 100% B with flow rate 1.5 mL/min; Detection: UV at 220 nm.

Method G: ACQUITY BEH C8 (2.1×50) mm, 1.7 micron column; Flow rate: 0.7mL/min;

Mobile Phase A: 5 mmol NH₄OAc in 95% Water/5% ACN; Mobile Phase B: 5mmol NH₄OAc in 5% Water/95% ACN; 20% B to 100% B over 1 min, then holdfor 0.6 min at 90% B; Detection: UV at 220 nm.

Method H: ACQUITY BEH C18 (2.1×50) mm, 1.7 micron column; Flow rate: 0.7mL/min; Mobile Phase A: 5 mmol NH₄OAc in 95% Water/5% ACN; Mobile PhaseB: 5 mmol NH₄OAc in 5% Water/95% ACN; 20% B to 100% B over 1 min, thenhold for 0.6 min. at 90% B; Detection: UV at 220 nm.Method I: ACQUITY BEH C18 (3×50) mm, 1.7 micron column; Flow rate: 0.7mL/min; Mobile Phase A: 5 mmol NH₄OAc in 95% Water/5% ACN; Mobile PhaseB: 5 mmol NH₄OAc in 5% Water/95% ACN; 20% B to 100% B over 1 min, thenhold for 0.6 min. at 90% B; Detection: UV at 220 nm.Method J: ACQUITY BEH C18 (2.1×50) mm, 1.7 micron column; Flow rate: 1.1mL/min; Mobile Phase A: 0.1% TFA in 95% Water/5% ACN; Mobile Phase B:0.1% TFA in 5% Water/95% ACN; 0% B to 98% B over 1.6 min, then hold for0.6 min. at 90% B; Detection: UV at 220 nm.Method K: Ascentis Express C18 (2.1×50) mm, 2.7 micron column; Flowrate: 1.1 mL/min; Mobile Phase A: 0.1% TFA in 95% Water/5% ACN; MobilePhase B: 0.1% TFA in 5% Water/95% ACN; 0% B to 100% B over 4 min,Detection: UV at 220 nm.Method L: Zorbax (3×50) mm, 1.7 micron column; Flow rate 1.5 mL/min;Mobile Phase A: 10 mmol NH₄OAc in 95% Water/5% ACN; Mobile Phase B: 10mmol NH₄OAc in 5% Water/95% ACN; 30% B to 100% B over 4.6 min, then holdfor 0.4 min. at 30% B; Detection: UV at 220 nm.Method M: X-Bridge BEH C18 (2.1×50) mm, 2.5 micron column; flow rate 0.5mL/min; Mobile Phase A: 5 mmol NH₄OAc in 95% Water/5% ACN; Mobile PhaseB: 5 mmol NH₄OAc in 5% Water/95% ACN; 20% B to 90% B over 2 min;Detection: UV at 220 nm.Method N: Zorbax SBC18 (4.6×50) mm, 5 micron column; Flow rate 1.5mL/min; Mobile Phase A: 10 mmol NH₄OAc in 98% Water/2% ACN; Mobile PhaseB: 10 mmol NH₄OAc in 2% Water/98% ACN; 30% B to 100% B over 4.6 min,then hold for 0.4 min at 30% B; Detection: UV at 254 nm.

Intermediate 1. Isopropyl(1S,3S)-3-((6-(4-(bromomethyl)-3-methylisoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

Intermediate 1A. (5-(5-bromopyridin-2-yl)-3-methylisoxazol-4-yl)methanol

A solution of 1M BH₃.THF in THF (14.8 mL, 14.8 mmol) was added dropwiseto a solution of 5-(5-bromopyridin-2-yl)-3-methylisoxazole-4-carboxylicacid (1.67 g, 5.90 mmol) (prepared according to the procedure ofNagasue, H., JP 2017095366) in THF (25 mL). The reaction was stirred at60° C. for 2 h, then was cooled to 0° C. and cautiously quenched withHOAc (1 mL) and MeOH (10 mL) at 0° C. The mixture was allowed to warm toRT and stirred at RT for 30 min, then was concentrated in vacuo. MeOH(30 ml) was added and the mixture was stirred for 30 min at RT, then wasconcentrated in vacuo. The residue was diluted with satd aq. NaHCO₃ (15mL) and extracted with EtOAc (5×20 mL). The combined organic extractswere washed with brine, dried (MgSO₄) and concentrated in vacuo. Thecrude product was chromatographed (40 g SiO₂, continuous gradient from 0to 100% EtOAc over 15 min) to afford the title compound (1.20 g, 4.5mmol, 76% yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 8.75 (dd,J=2.3, 0.7 Hz, 1H), 8.05 (dd, J=8.5, 2.4 Hz, 1H), 7.90 (dd, J=8.5, 0.8Hz, 1H), 4.63 (s, 2H), 2.36 (s, 3H). LCMS, [M+H]⁺=269.

Intermediate 1B.5-(5-bromopyridin-2-yl)-3-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazole

p-TsOH.H₂O (18 mg, 0.096 mmol) was added to a 0° C. solution ofintermediate 1A (516 mg, 1.918 mmol) and 3,4-dihydro-2H-pyran (0.53 mL,5.75 mmol) in DCM (6 mL). The reaction was stirred for 48 h at RT, thenwas cooled to 0° C. and neutralized with satd aq. NaHCO₃ to pH˜7. Themixture was partitioned between DCM (10 mL) and water (10 mL); theaqueous layer was extracted with DCM (3×10 mL). The combined organicextracts were dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (40 g SiO₂, continuous gradient from 0 to 50%EtOAc/hexanes over 15 min) to afford the title compound (640 mg, 1.812mmol, 94% yield) as a colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 8.74 (dd,J=2.4, 0.8 Hz, 1H), 7.93 (dd, J=8.5, 2.3 Hz, 1H), 7.79 (dd, J=8.5, 0.8Hz, 1H), 5.03 (d, J=12.1 Hz, 1H), 4.93 (d, J=12.1 Hz, 1H), 4.74 (t,J=3.6 Hz, 1H), 3.91 (ddd, J=11.5, 8.5, 3.1 Hz, 1H), 3.59-3.45 (m, 1H),2.42 (s, 3H), 1.86-1.49 (m, 6H). LCMS, [M+H]⁺=353.3.

Intermediate 1C.6-(3-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazol-5-yl)pyridin-3-ol

A mixture of Pd₂(dba)₃ (100 mg, 0.109 mmol),di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (185mg, 0.435 mmol), KOH (610 mg, 10.87 mmol) and intermediate 1B (640 mg,1.81 mmol) in 1,4-dioxane (5 mL) and water (5 mL) was quickly evacuatedand backfilled with argon (repeated 3×). The mixture was stirred at 85°C. for 14 h, then was cooled to RT and carefully acidified with aq. 1NHCl to pH˜4. EtOH (2 mL) was added and the mixture was extracted withEtOAc (8×5 mL). The combined organic extracts were dried (MgSO₄) andconcentrated in vacuo. The crude residue was chromatographed (40 g SiO₂,continuous gradient from 0 to 100% EtOAc in hexanes over 14 min) toafford the title compound (275 mg, 0.947 mmol, 52.3% yield) as aslightly colored oil. ¹H NMR (500 MHz, CDCl₃) δ 8.33 (d, J=2.8 Hz, 1H),7.72 (d, J=8.6 Hz, 1H), 7.26 (dd, J=8.6, 2.8 Hz, 1H), 5.02 (d, J=11.9Hz, 1H), 4.91 (d, J=12.0 Hz, 1H), 4.77 (dd, J=4.5, 2.9 Hz, 1H), 3.94(ddd, J=11.5, 8.0, 3.2 Hz, 1H), 3.55 (dtd, J=10.7, 4.7, 4.2, 2.3 Hz,1H), 2.40 (s, 3H), 1.86-1.45 (m, 6H). LCMS, [M+11]⁺=291.1.

Intermediate 1D. Isopropyl(1S,3S)-3-((6-(3-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a 0° C. mixture of intermediate 1C (275 mg, 0.947 mmol),(1S,3R)-isopropyl 3-hydroxycyclo-hexanecarboxylate (318 mg, 1.71 mmol),Et₃N (0.238 mL, 1.71 mmol) and PPh₃ (447 mg, 1.71 mmol) in THF (4 mL)was added DIAD (0.33 mL, 1.71 mmol) dropwise over 5 min. The reactionwas stirred at RT for 5 days, then was diluted with H₂O (3 mL) andextracted with EtOAc (3×5 mL). The combined organic extracts were dried(MgSO₄) and concentrated in vacuo. The crude product was chromatographed(40 g SiO₂, continuous gradient from 0 to 60% EtOAc/hexanes over 20 min)to afford the title compound (217 mg, 0.47 mmol, 50% yield) as aslightly colored oil. ¹H NMR (500 MHz, CDCl₃) δ 8.37 (d, J=2.9 Hz, 1H),7.82 (d, J=8.8 Hz, 1H), 7.31 (dd, J=8.8, 3.0 Hz, 1H), 5.08-4.97 (m, 2H),4.96-4.90 (m, 1H), 4.77-4.66 (m, 2H), 3.93 (ddd, J=11.7, 8.4, 3.2 Hz,1H), 3.57-3.46 (m, 1H), 2.80 (tt, J=8.7, 4.4 Hz, 1H), 2.40 (s, 4H),2.03-1.48 (m, 14H), 1.25 (dd, J=6.2, 2.4 Hz, 6H). LCMS, [M+H]⁺=459.3.

Intermediate 1E. isopropyl(1S,3S)-3-((6-(4-(hydroxymethyl)-3-methylisoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a solution of intermediate 1D (175 mg, 0.38 mmol) in MeOH (3 mL) wasadded PPTS (9.6 mg, 0.038 mmol). The mixture was heated at 60° C. for 2h, then was cooled to RT, quenched with sat'd aq. NaHCO₃(2 mL) andconcentrated in vacuo to remove the MeOH. The residue was extracted withEtOAc (3×5 mL). The combined organic extracts were dried (MgSO₄) andconcentrated in vacuo. The crude product was chromatographed (12 g SiO₂;continuous gradient from 0% to 100% EtOAc:hexanes over 11 min) to affordthe title compound (75 mg, 53% yield) as a white solid. ¹H NMR (500 MHz,CDCl₃) δ 8.35 (d, J=2.9 Hz, 1H), 7.93 (d, J 8.7 Hz, 1H), 7.44 (dd,J=8.8, 2.9 Hz, 1H), 6.14 (t, J=6.8 Hz, 1H), 5.04 (hept, J=6.2 Hz, 1H),4.74 (dp, J=5.8, 2.8 Hz, 1H), 4.60 (d, J=6.7 Hz, 2H), 2.80 (tt, J=8.7,4.2 Hz, 1H), 2.34 (s, 3H), 2.08-1.55 (m, 8H), 1.22 (d, J=6.2 Hz, 6H).LCMS, [M+H]⁺=375.2.

Intermediate 1

PBr₃ (0.16 mL, 1.67 mmol) was added to a solution of intermediate 1E(208 mg, 0.556 mmol) in DME (4 mL) at 0° C. The reaction was stirred for1 h at RT, then was cooled to 0° C. and neutralized with satd aq NaHCO₃to pH 7. The mixture was partitioned between DCM (5 mL) and H₂O (3 mL);the aqueous layer was extracted with CH₂Cl₂ (3×5 mL). The combinedorganic extracts were dried (MgSO₄) and concentrated in vacuo. The crudeproduct was chromatographed (12 g SiO₂, continuous gradient from 0% to60% EtOAc:Hexanes over 11 min) to afford the title compound (198 mg,0.45 mmol, 80% yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 8.43(d, J=2.9 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.36 (dd, J=8.8, 2.9 Hz, 1H),5.06 (dq, J=12.5, 6.3 Hz, 1H), 5.01 (s, 2H), 4.76 (qd, J=5.5, 4.8, 2.5Hz, 1H), 2.82 (dtd, J=8.8, 6.5, 4.1 Hz, 1H), 2.42 (s, 3H), 2.07-1.57 (m,8H), 1.27 (dd, J=6.3, 2.9 Hz, 6H). LCMS, [M+H]⁺=438.0.

Intermediate 2. Isopropyl(1S,3S)-3-((6-(4-(aminomethyl)-3-methylisoxazol-5-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate

Intermediate 2A. tert-butyl(E)-2-(5-bromo-6-methylpicolinoyl)-3-(methylimino)butanoate

To a suspension of 5-bromo-6-methylpicolinoyl chloride (7.97 g, 34 mmol)and (E)-tert-butyl 3-(methylimino)butanoate (6.40 g, 37.4 mmol) in THF(100 mL) at 0° C. was added pyridine (13.75 mL, 170 mmol) dropwise. Thereaction mixture was slowly warmed to RT and stirred at RT for 16 h,then was partitioned between EtOAc (100 mL) and water (100 mL). Theaqueous phase was extracted with EtOAc (2×100 mL). The combined organicextracts were dried (MgSO₄) and concentrated in vacuo to give the crudetitle compound (13.0 g, 104% yield) as a yellow oil. LCMS, [M+H]⁺=369.2.

Intermediate 2B. tert-butyl5-(5-bromo-6-methylpyridin-2-yl)-3-methylisoxazole-4-carboxylate

A mixture of Intermediate 2A (12.55 g, 34 mmol) and NH₂OH.HCl (3.54 g,51.0 mmol) in EtOH (136 mL) was stirred at 60° C. for 20 h, then wascooled to RT. Volatiles were removed in vacuo. The residue waspartitioned between EtOAc (50 mL) and aq. satd Na₂CO₃ (50 mL) and water.The organic layer was washed with water (50 mL) and brine (50 mL), dried(MgSO₄) and concentrated in vacuo. The crude product was chromatographed(750 g SiO₂; continuous gradient from 0% to 20% EtOAc/DCM over 10 min)to afford the title compound (6.73 g, 19 mmol, 56% yield) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J=8.2 Hz, 1H), 7.63 (d, J=8.3Hz, 1H), 2.77 (s, 3H), 2.51 (s, 3H), 1.57 (s, 9H).). LCMS, [M+H]⁺=352.9.

Intermediate 2C,5-(5-bromo-6-methylpyridin-2-yl)-3-methylisoxazole-4-carboxylic Acid

TFA (20 mL) was added dropwise to a solution of Intermediate 2B (3.0 g,8.49 mmol) in DCM (40 ml) at RT. The reaction mixture was stirred at RTfor 2 h, then was concentrated in vacuo to give the title compound (2.52g, 8.49 mmol, 100% yield) as a brown solid. ¹H NMR (500 MHz, CDCl₃) δ8.21 (d, J=8.3 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 2.80 (s, 3H), 2.64 (s,3H). LCMS, [M+H]⁺=297.1.

Intermediate 2D.(5-(5-bromo-6-methylpyridin-2-yl)-3-methylisoxazol-4-yl)methanol

To a 0° C. solution of Intermediate 2C (2.52 g, 8.49 mmol) in THF (50mL) was added 1M BH₃.THF in THF (21.2 mL, 21.2 mmol) dropwise. Uponcompletion of the addition, the reaction was heated at 60° C. for 2 h,then was cooled to RT. The reaction mixture was quenched with HOAc (1mL) and MeOH (10 mL). The mixture was stirred at RT for 30 min then wasconcentrated in vacuo. The crude product was chromatographed (80 g SiO₂;continuous gradient from 0 to 50% EtOAc/hexanes over 20 min, hold at 50%EtOAc for 10 min) to give the title compound (1.45 g, 5.12 mmol, 60.3yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 8.01 (d, J=8.3 Hz,1H), 7.71 (d, J=8.3 Hz, 1H), 5.93 (t, J=6.8 Hz, 1H), 4.62 (d, J=6.8 Hz,2H), 2.75 (s, 3H), 2.36 (s, 3H). LCMS, [M+H]⁺=283.1.

Intermediate 2E.5-(5-bromo-6-methylpyridin-2-yl)-3-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl) isoxazole

To a RT solution of Intermediate 2D (1.45 g, 5.12 mmol) in DCM (30 mL)was added 3,4-dihydro-2H-pyran (1.17 mL, 12.8 mmol) and PPTS (64 mg,0.26 mmol). The reaction was stirred at RT overnight, then was quenchedwith satd aq. NaHCO₃ was extracted with EtOAc (2×). The combined organicextracts were washed with H₂O, brine, dried (MgSO₄), and concentrated invacuo. The residue was chromatographed (120 g SiO₂; continuous gradientfrom 0-30% EtOAc/hexanes over 35 min) to give the title compound (1.4 g,74% yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 7.90 (d, J=8.3Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 5.09-4.94 (m, 2H), 4.75 (t, J=3.6 Hz,1H), 3.91 (ddd, J=11.6, 8.6, 3.1 Hz, 1H), 3.58-3.46 (m, 1H), 2.70 (s,3H), 2.41 (s, 3H), 1.85-1.48 (m, 8H). LCMS, [M+H]⁺=367.2.

Intermediate 2F.2-methyl-6-(3-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazol-5-yl)pyridin-3-ol

To a solution of KOH (0.642 g, 11.4 mmol) in H₂O (10 mL) were addedIntermediate 2E (1.40 g, 3.81 mmol) and 1,4-dioxane (10 mL). Thesolution was degassed with N₂, thendi-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphane(0.259 g, 0.61 mmol) and Pd₂dba₃ (0.140 g, 0.152 mmol) were added. Thereaction mixture was degassed with N₂ and stirred at 85° C. overnight,then was cooled to RT, acidified with 1N aq. HCl and extracted withEtOAc (2×). The combined organic extracts were washed with H₂O, brine,dried (MgSO₄) and concentrated in vacuo. The residue was chromatographed(80 g SiO₂; continuous gradient from 0-50% EtOAc/hexanes over 20 min,then hold at 50% EtOAc/hexanes for 15 min) to give the title compound(760 mg, 2.50 mmol, 65.5% yield) as a beige solid. ¹H NMR (500 MHz,CDCl₃) δ 7.56 (d, J=8.4 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.54 (s, 1H),5.07 (d, J=11.8 Hz, 1H), 4.99 (d, J=11.8 Hz, 1H), 4.78 (dd, J=4.3, 3.0Hz, 1H), 3.95 (ddd, J=11.6, 8.3, 3.1 Hz, 1H), 3.56 (dt, J=10.6, 4.9 Hz,1H), 2.51 (s, 3H), 2.40 (s, 3H), 1.87-1.48 (m, 6H). LCMS [M+H]⁺=305.3.

Intermediate 2G. Isopropyl(1S,3S)-3-((2-methyl-6-(3-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl) isoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

A solution of (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (1.26 g,5.0 mmol) and Bu₃P (1.25 mL, 5.0 mmol) in 1,4-dioxane (20 mL) wasstirred at RT for 30 min. Intermediate 2F (760 mg, 2.50 mmol) andisopropyl (1S,3R)-3-hydroxycyclohexane-1-carboxylate (837 mg, 4.49 mmol)were successively added. The reaction mixture was heated to 85° C. for 9h under 1 atm of N₂, then was cooled to RT and diluted with DCM (10 mL).The mixture was filtered and the filtrate was concentrated in vacuo. Thecrude oil was chromatographed (80 g SiO₂; continuous gradient from 0-50%EtOAc/hexanes over 25 min, hold at 50% for 20 min) to give the titlecompound (618 mg, 1.308 mmol, 52.4% yield) as a light yellow oil. LCMS[M+H]⁺=473.2.

Intermediate 2H. Isopropyl(1S,3S)-3-((6-(4-(hydroxymethyl)-3-methylisoxazol-5-yl)-2-methyl-pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a solution of Intermediate 2G (618 mg, 1.31 mmol) in MeOH (12 mL) wasadded PPTS (49 mg, 0.20 mmol). The reaction was heated at 60° C.overnight, then was cooled to RT, neutralized with satd aq. NaHCO₃ andconcentrated in vacuo. The mixture was diluted with H₂O and extractedwith EtOAc (2×). The combined organic extracts were washed with H₂O,dried (MgSO₄), and concentrated in vacuo. The residue waschromatographed (40 g SiO₂; continuous gradient from 0-100%EtOAc/hexanes over 15 min, and hold for 10 min) to give the titlecompound (460 mg, 91% yield) as a white solid. LCMS, [M+H]⁺=389.2.

Intermediate 2I. Isopropyl(1S,3S)-3-((6-(4-(bromomethyl)-3-methylisoxazol-5-yl)-2-methyl-pyridin-3-yl)oxy)cyclohexane-1-carboxylate

PBr₃ (0.21 mL, 2.25 mmol) was added to a solution of Intermediate 2H(350 mg, 0.90 mmol) in DME (8 mL) at 0° C. The reaction was stirredovernight at RT, then was cooled to 0° C. and neutralized with withsat'd aq. NaHCO₃. The mixture was partitioned between DCM (10 mL) andH₂O (5 mL), and the aqueous layer was extracted with DCM (3×5 mL). Thecombined organic extracts were dried (MgSO₄), and concentrated in vacuo.The crude product was chromatographed (40 g SiO₂; continuous gradientfrom 0% to 20%: EtOAc/hexanes over 20 min) to afford the title compound(355 mg, 0.79 mmol, 87% yield) as a white solid. LCMS [M+H]⁺=451.0.

Intermediate 2J. Isopropyl(1S,3S)-3-((6-(4-(azidomethyl)-3-methylisoxazol-5-yl)-2-methyl-pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a solution of Intermediate 2I (350 mg, 0.78 mmol) in DMF (6 mL) wasadded NaN₃ (50 mg, 0.78 mmol). The reaction was stirred at 80° C. for 1h, then was cooled to RT and EtOAc and H₂O were added (10 mL each). Theresulting mixture was stirred at RT for 15 min, after which the organiclayer was dried (Na₂SO₄) and concentrated in vacuo to afford the titlecompound (320 mg, 0.78 mmol, 100% yield) as a white solid. LCMS,[M+H]⁺=414.1.

Intermediate 2

To a solution of Intermediate 2J (320 mg, 0.775 mmol) in THF (5 mL) andH₂O (1.67 mL) was added Ph₃P (203 mg, 0.775 mmol) and the reaction wasstirred at RT overnight, after which EtOAc and brine were added (10 mLeach). The mixture was stirred at RT for 5 min, after which the organiclayer was separated, dried (Na₂SO₄), and concentrated in vacuo. Theresidue was chromatographed (12 g SiO₂; 0% to 10% MeOH/CH₂Cl₂ for 20min.; flow rate=30 mL/min) to give the title compound (290 mg, 0.748mmol, 97% yield) as a light brown oil. LCMS [M+H]⁺=388.2. ¹H NMR (500MHz, CDCl₃) δ 7.74 (d, J=8.5 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 5.10-5.00(m, 1H), 4.78-4.70 (m, 1H), 3.93 (s, 2H), 2.83-2.73 (m, 1H), 2.56 (s,3H), 2.37 (s, 3H), 2.14-1.58 (m, 8H), 1.27 (dd, J=6.3, 2.2 Hz, 6H).

Intermediate 3. (1S,3S)-isopropyl3-(4-(4-(hydroxymethyl)-3-methylisoxazol-5-yl)phenoxy)cyclo-hexane-1-carboxylate

Intermediate 3A. (5-(4-bromophenyl)-3-methylisoxazol-4-yl)methanol

To a solution of 5-(4-bromophenyl)-3-methylisoxazole-4-carboxylic acid(synthesized according to the procedure described in US2011/82164 A1,2.0 g, 7.09 mmol) in THF (50 mL) was added BH₃.THF (28.4 mL of a 1Msolution in THF, 28.4 mmol) portionwise at 0° C. and the solution wasallowed to warm to RT and stirred overnight at RT. The reaction mixturewas carefully quenched with H₂O, acidified with 1N aq. HCl (50 mL),stirred for 1 h at RT, then was extracted with EtOAc (2×). The combinedorganic extracts were washed with H₂O, brine, dried (MgSO₄), andconcentrated in vacuo. The residue was chromatographed (SiO₂; continuousgradient from 35-75% EtOAc in Hexanes) to give the title compound (1.65g, 87% yield) as a white solid. LCMS [M+H]⁺=268. ¹H NMR (CDCl₃, 400 MHz)δ 7.73-7.64 (m, 4H), 4.66 (d, J=5.1 Hz, 2H), 2.42 (s, 3H).

Intermediate 3B.5-(4-bromophenyl)-3-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazole

To a solution of Intermediate 3A (626 mg, 2.33 mmol) in CH₂Cl₂ (10 mL)was added 3,4-dihydro-2H-pyran (0.64 mL, 7.0 mmol) and PPTS (29 mg, 0.12mmol). After stirring overnight at RT, the mixture was quenched withsat. aq. NaHCO₃ and extracted with EtOAc (2×). The combined organicextracts were washed with H₂O, brine, dried (MgSO₄), and concentrated invacuo. The residue was chromatographed (SiO₂; continuous gradient from35-100% EtOAc/Hexanes) to give the title compound (811 mg, 99% yield) asa white solid. LCMS [M+H]⁺=358. ¹H NMR (500 MHz, CDCl₃) δ 7.82-7.55 (m,4H), 4.69 (m, 1H), 4.65 (m, 1H), 4.46 (m, 1H), 3.87 (m, 1H), 3.54 (m,1H), 2.37 (s, 3H), 1.86-1.55 (m, 6H).

Intermediate 3C.4-(3-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazol-5-yl)phenol

To a solution of KOH (2.70 g, 48.1 mmol) in H₂O (50 mL) weresuccessively added Intermediate 3B (5.65 g, 16.0 mmol) and 1,4-dioxane(50 mL) and the solution was degassed with N₂. t-BuXphos (0.545 g, 1.28mmol) and Pd₂(dba)₃ (0.294 g, 0.321 mmol) were added and the suspensionwas degassed with N₂, then was stirred at 90° C. overnight. The reactionmixture was cooled to RT, acidified with 1N aq. HCl and extracted withEtOAc (2×). The combined organic extracts were washed with H₂O, brine,dried (MgSO₄), and concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 25-75% EtOAc/hexanes) togive the title compound (3.63 g, 78% yield) as a white solid. LCMS[M+H]⁺=290. ¹H NMR (500 MHz, CDCl₃) δ 7.72 (d, J=8.8 Hz, 2H), 6.94 (d,J=8.8 Hz, 2H), 4.70 (m, 1H), 4.66 (d, J=12.4 Hz, 1H), 4.48 (d, J=12.4Hz, 1H), 3.89 (m, 1H), 3.53 (m, 1H), 2.36 (s, 3H), 1.88-1.70 (m, 2H),1.65-1.57 (m, 4H).

Intermediate 3D. (1S,3S)-isopropyl3-(4-(3-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazol-5-yl)phenoxy)cyclohexane-1-carboxylate

To a RT solution of Intermediate 3C (500 mg, 1.73 mmol),(1S,3R)-isopropyl 3-hydroxy cyclohexanecarboxylate (547 mg, 2.94 mmol),Et₃N (0.41 mL, 2.94 mmol) and Ph₃P (770 mg, 2.94 mmol) in THF (10 mL)was added DEAD (1.34 mL, 2.94 mmol) portionwise over 15 min. Thereaction mixture was stirred at RT for 2 days, then was concentrated invacuo, diluted with H₂O, acidified with 1N aq. HCl and extracted withEtOAc (2×). The combined organic extracts were washed with H₂O, brine,dried (MgSO₄), and concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 15-70% EtOAc/Hexanes) togive the title compound (458 mg, 58% yield) as a white solid. LCMS[M+H]⁺=458. ¹H NMR (500 MHz, CDCl₃) δ 7.75 (d, J=8.8 Hz, 2H), 7.03 (d,J=8.8 Hz, 2H), 5.02 (m, 1H), 4.70 (m, 1H), 4.66 (d, J=12.4 Hz, 1H), 4.48(d, J=12.4 Hz, 1H), 3.88 (m, 1H), 3.54 (m, 1H), 2.80 (m, 1H), 2.35 (s,3H), 2.08-1.97 (m, 2H), 1.93-1.80 (m, 3H), 1.78-1.52 (m, 10H), 1.24 (m,6H).

Intermediate 3

To a RT solution of Intermediate 3D (458 mg, 1.00 mmol) in MeOH (10 mL)was added PPTS (25 mg, 0.10 mmol). The reaction was stirred at RTovernight, then was heated at 50° C. for 2 h and cooled to RT. Themixture was basified to pH=7 with sat aq. NaHCO₃ and concentrated invacuo. The mixture was diluted with H₂O and extracted with EtOAc (2×).The combined organic extracts were washed with H₂O, dried (MgSO₄), andconcentrated in vacuo. The residue was chromatographed (SiO₂; continuousgradient from 15-70% EtOAc/Hexanes) to give the title compound (263 mg,70% yield) as a white solid. LCMS [M+H]⁺=374. ¹H NMR (500 MHz, CDCl₃) δ7.71 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 5.42 (s, 2H), 5.05 (m,1H), 4.74 (m, 1H), 2.83 (m, 1H), 2.45 (s, 3H), 2.04 (m, 2H), 1.92 (m,2H), 1.82-1.58 (m, 5H), 1.27 (dd, J=6.3, 1.4 Hz, 6H).

Intermediate 4. (1S,3S)-Ethyl3-((6-(4-(hydroxymethyl)-3-methylisoxazol-5-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate

Intermediate 4A. Tert-Butyl5-(5-bromo-6-methylpyridin-2-yl)-3-methylisoxazole-4-carboxylate

To a 0° C. solution of 5-bromo-6-methylpicolinic acid (3.0 g, 13.9 mmol)in CH₂Cl₂ (25 mL) and DMF (1 mL) under N₂ was added SOCl₂ (3.0 mL, 41.7mmol) and the reaction mixture was warmed to RT and stirred at 55° C.for 15 h (no starting material remaining by LC-MS at this time). Thereaction mixture was cooled to RT and concentrated in vacuo. The crudeacid chloride product was dissolved in THF (10 mL) and a solution oftert-butyl 3-(methylamino)but-2-enoate (4.67 g, 27.3 mmol) and pyridine(2.2 mL, 27.3 mmol) in THF (10 mL) was added slowly at RT. The reactionmixture was stirred at RT for 24 h (no starting material remaining byLC-MS at this point), then was concentrated in vacuo. The residual crudeproduct was dissolved in EtOH (40 mL) and water (2 mL) and NH₂OH.H₂O(1.98 g, 41.7 mmol) was added. The reaction mixture was stirred at 60°C. for 15 h, then was cooled to RT and concentrated in vacuo. Water (50mL) was added and the mixture was extracted with EtOAc (2×50 mL). Thecombined organic extracts were washed with brine (50 mL), dried (Na₂SO₄)and concentrated in vacuo. The crude product was chromatographed (24 gRedisep® SiO₂ column, 10% EtOAc in n-hexanes) to afford the titlecompound (2.55 g, 52%, for 3 steps) as an orange liquid. LCMS retentiontime=1.42 min; m/z=355.0 [M+H]⁺ (Method M). ¹H NMR (300 MHz, CDCl₃) δ8.16 (d, J=8.10 Hz, 1H), 7.67 (d, J=8.10 Hz, 1H), 2.73 (s, 3H), 2.48 (s,3H), 1.49 (s, 9H).

Intermediate 4B.5-(5-Bromo-6-methylpyridin-2-yl)-3-methylisoxazole-4-carboxylic acid

To a solution of Intermediate 4A (2.50 g, 7.08 mmol) in CH₂Cl₂ (4 mL)was added TFA (3.82 mL, 49.5 mmol) and the reaction mixture was stirredat RT for 15 h, then was concentrated in vacuo to afford the titlecompound (1.75 g, 83%) as a yellow solid. LCMS retention time=0.67 min;m/z=297.3 [M+H]⁺ (Method I). ¹H NMR (400 MHz, CDCl₃) δ 8.21 (d, J=8.80Hz, 1H), 7.92 (d, J=8.80 Hz, 1H), 2.79 (s, 3H), 2.63 (s, 3H).

Intermediate 4C.(5-(5-Bromo-6-methylpyridin-2-yl)-3-methylisoxazol-4-yl)methanol

To a 0° C. solution of Intermediate 4B (1.50 g, 5.05 mmol) in THF (80mL) were added ethyl chloroformate (1.64 g, 15.2 mmol) and Et₃N (1.41mL, 10.1 mmol) and the reaction was allowed to warm to RT and stirred atRT for 16 h. The reaction mixture was filtered through Celite® and thefiltrate was concentrated in vacuo. The residue was dissolved in EtOH(15 mL), cooled to 0° C. and NaBH₄ (0.573 g, 15.2 mmol) was added. Thereaction mixture was allowed to warm to RT and stirred at RT for 1 h,then was quenched with 0° C. aq. 1.5 N HCl (50 mL) and extracted withCH₂Cl₂ (2×50 mL). The combined organic extracts were washed with brine(50 mL), dried (Na₂SO₄) and concentrated in vacuo. The crude product waschromatographed (12 g Redisep® SiO₂ column, eluting with 20% EtOAc inn-hexanes) to afford the title compound (1.22 g, 85%) as a white solid.LCMS retention time=1.25 min; m/z=283.2 [M+H]⁺ (Method H). ¹H NMR (300MHz, CDCl₃) δ ppm 8.00 (d, J=8.40 Hz, 1H), 7.70 (d, J=8.40 Hz, 1H), 4.62(s, 2H), 2.75 (s, 3H), 2.36 (s, 3H).

Intermediate 4D.5-(5-bromo-6-methylpyridin-2-yl)-3-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazole

To a solution of Intermediate 4C (1.20 g, 4.24 mmol) in dioxane (15 mL)was added 3,4-dihydro-2H-pyran (0.463 g, 5.5 mmol) and PPTS (0.533 g,2.12 mmol). The reaction mixture was stirred at RT for 15 h, then wasdiluted with water (20 mL) and extracted with EtOAc (2×30 mL). Thecombined organic extracts were washed with brine (30 mL), dried (Na₂SO₄)and concentrated in vacuo. The crude product was chromatographed (24 gRedisep® SiO₂ column, eluting with 20% EtOAc in hexanes) to give thetitle compound (1.30 g, 84%) as a colorless liquid. LCMS retentiontime=3.32 min; m/z=367.2 [M+H]⁺ (Method E). ¹H NMR (400 MHz, CDCl₃) δppm 7.91 (d, J=8.40 Hz, 1H), 7.59 (d, J=8.40 Hz, 1H), 5.02 (ABq, J=11.60Hz, 2H), 4.75 (t, J=3.60 Hz, 1H), 4.00-4.10 (m, 1H), 3.80-3.95 (m, 1H),2.70 (s, 3H), 2.41 (s, 3H), 1.40-1.90 (m, 6H).

Intermediate 4E.3-Methyl-5-(6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazole

To a degassed mixture of Intermediate 4D (1.30 g, 3.54 mmol),bis(pinacolato)diboron (1.80 g, 7.08 mmol) and KOAc (0.695 g, 7.08 mmol)in dioxane (40 mL) was added 1,1′-bis(diphenyl-phosphino)ferrocenepalladium(II)dichloride-CH₂Cl₂ adduct (0.578 g, 0.708 mmol). Thereaction mixture was heated at 90° C. for 8 h, then was cooled to RT andfiltered through a Celite pad. The Celite/solids were washed withadditional EtOAc (50 mL) and the combined filtrates were concentrated invacuo to give the title compound (1.25 g, 85%) as a colorless oil. Thiscrude product was used in the next reaction without furtherpurification. LC-MS retention time=3.93 min; m/z=415.2 [M+H]⁺ (MethodE).

Intermediate 4F.2-Methyl-6-(3-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazol-5-yl)pyridin-3-ol

To a solution of crude Intermediate 4E (1.25 g, 3.02 mmol) in THF (15mL) and water (2 mL) was added NABO₃.H₂O (1.21 g, 12.1 mmol) and thereaction mixture was stirred at 55° C. for 90 min, then was cooled toRT. The reaction mixture was diluted with EtOAc (80 mL), washed withwater (2×50 mL), dried (Na₂SO₄) and concentrated in vacuo. The crudeproduct was chromatographed (24 g Redisep® SiO₂ column, eluting with 25%EtOAc in hexane) to afford the title compound (0.78 g, 85%) as acolorless oil. LCMS retention time=1.14 min; m/z=303.4 [M−H] (Method I).¹H NMR (300 MHz, DMSO-d₆) δ 10.44 (s, 1H), 7.59 (d, J=8.40 Hz, 1H), 7.25(d, J=8.40 Hz, 1H), 5.03 (ABq, J=12.40 Hz, 2H), 4.70 (br. s., 1H),3.75-3.90 (m, 1H), 3.40-3.50 (m, 1H), 2.39 (s, 3H), 2.29 (s, 3H),1.35-1.80 (m, 6H).

Intermediate 4G. (1S,3S)-Ethyl3-((2-methyl-6-(3-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazol-5-yl) pyridin-3-yl)oxy)cyclohexanecarboxylate

To a solution of Intermediate 4F (0.78 g, 2.56 mmol) in toluene (8 mL)was added di-tert-butyl azodicarboxylate (1.48 g, 6.41 mmol) and Ph₃P(1.68 g, 6.41 mmol). The mixture was stirred at RT for 5 min, afterwhich (1S,3R)-ethyl 3-hydroxycyclohexanecarboxylate (0.75 g, 4.36 mmol)was added. The reaction mixture was stirred at 75° C. for 20 h, then wascooled to RT and concentrated in vacuo. The crude product waschromatographed (24 g Redisep® SiO₂ column, eluting with 15% EtOAc inhexanes) to afford the title compound (0.68 g, 58%) as a colorless oil.LCMS retention time=1.72 min; m/z=459.2 [M+H]⁺ (Method I). ¹H NMR (400MHz, CDCl₃) δ 7.67 (d, J=8.80 Hz, 1H), 7.18 (d, J=8.80 Hz, 1H), 4.99 (s,2H), 4.65-4.75 (m, 2H), 4.11 (q, J=7.20 Hz, 2H), 3.88-3.98 (m, 1H),3.45-3.58 (m, 1H), 2.75-2.85 (m, 1H), 2.51 (s, 3H), 2.38 (s, 3H),2.00-2.15 (m, 1H) 1.80-2.00 (m, 3H), 1.40-1.75 (m, 10H), 1.23 (t, J=7.20Hz, 3H).

Intermediate 4

To a solution of Intermediate 3G (680 mg, 1.483 mmol) in MeOH (5 mL) wasadded pTsOH.H₂O (141 mg, 0.741 mmol) and the reaction mixture wasstirred at RT for 3 h, then was concentrated in vacuo. The crude productwas chromatographed (12 g Redisep® SiO₂ column, eluting with 30% EtOAcin hexanes) to give the title compound (340 mg, 61%) as a colorless oil.LC-MS retention time=1.38 min; m/z=375.5 [M+H]⁺ (Method I). ¹H NMR (400MHz, CDCl₃) δ ppm 7.78 (d, J=8.40 Hz, 1H), 7.29 (d, J=8.40 Hz, 1H), 6.57(t, J=6.80 Hz, 1H), 4.74 (br. s., 1H), 4.60 (d, J=6.40 Hz, 2H), 4.15 (q,J=7.2 Hz, 2H), 2.75-2.85 (m, 1H), 2.54 (s, 3H), 2.32 (s, 3H), 1.85-2.10(m, 4H), 1.60-1.75 (m, 4H), 1.27 (t, J=7.2 Hz, 3H).

Intermediate 5. (±)-cis-isopropyl1-fluoro-3-hydroxycyclohexanecarboxylate

Intermediate 5A. (±)-ethyl 1-fluorocyclohex-3-enecarboxylate

A mixture of 20% buta-1,3-diene in toluene (13.8 mL, 41.1 mmol) andethyl 2-fluoroacrylate (3.07 mL, 27.4 mmol) was heated at 120° C. in asealed tube for 7 days. The reaction was cooled to RT and concentratedin vacuo. The residue was chromatographed (80 g SiO₂; continuousgradient from 0% to 10% EtOAc in hexane over 20 min) to give the titlecompound (3.80 g, 22.1 mmol, 80% yield) as a clear oil. ¹H NMR (500 MHz,CDCl₃) δ 5.79 (ddd, J=9.9, 4.7, 2.2 Hz, 1H), 5.64-5.58 (m, 1H), 4.26 (q,J=7.2 Hz, 2H), 2.73-2.57 (m, 1H), 2.45-2.23 (m, 2H), 2.20-1.91 (m, 3H),1.32 (t, J=7.2 Hz, 3H); ¹⁹F NMR (471 MHz, CDCl₃) δ −162.69 (s, 1F).

Intermediate 5B. (±)-1-fluorocyclohex-3-ene Carboxylic Acid

A mixture of Intermediate 5A (3.80 g, 22.1 mmol) and aq. LiOH (55.2 mLof a 2.0 M solution, 110 mmol) in THF (50 mL) was stirred at rt for 18h. The reaction was acidified to pH=2 with conc. HCl (9.19 mL, 110mmol), and then extracted with EtOAc (3×25 mL). The combined organicextracts were washed with water and concentrated in vacuo to give thetitle compound (3.0 g, 20.8 mmol, 94% yield) as a light yellowish oil.¹H NMR (500 MHz, CDCl₃) δ 5.81 (ddd, J=9.8, 4.6, 2.1 Hz, 1H), 5.66-5.58(m, 1H), 2.76-2.59 (m, 1H), 2.49-2.37 (m, 1H), 2.35-2.23 (m, 1H),2.22-1.92 (m, 3H); ¹⁹F NMR (471 MHz, CDCl₃) δ −163.02 (s, 1F).

Intermediate 5C. (±)-1-fluoro-4-iodo-6-oxabicyclo[3.2.1]octan-7-one

To a mixture of Intermediate 5B (3.0 g, 20.8 mmol) in water (20 mL) wasadded NaHCO₃(5.25 g, 62.4 mmol) portionwise and the mixture was stirreduntil it became homogeneous. An aq. 12 solution (prepared by dissolving12 (5.81 g, 22.0 mmol) and KI (20.7 g, 125 mmol) in 20 mL water) wasadded and the reaction was stirred overnight at rt in the dark. Water(100 mL) was then added and the mixture was extracted with DCM (3×25mL), washed with 10% aq. Na₂S₂O₃ (20 mL×2) and water, dried (MgSO₄) andconcentrated in vacuo. The residual crude oil was chromatographed (80 gSiO₂; continuous gradient from 0% to 50% EtOAc in Hexane over 20 min) togive the title compound (3.53 g, 13.1 mmol, 62.8% yield) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ 4.89 (dt, J=6.5, 3.5 Hz, 1H), 4.44 (q,J=4.6 Hz, 1H), 3.08 (dd, J=11.6, 1.9 Hz, 1H), 2.75 (tddd, J=11.3, 6.5,3.3, 1.1 Hz, 1H), 2.50-2.38 (m, 1H), 2.34-2.17 (m, 2H), 2.11-1.99 (m,1H); ¹³C NMR (126 MHz, CDCl₃) δ 172.2, 172.0, 93.6, 91.9, 78.4, 78.3,39.2, 39.0, 29.7, 29.6, 28.4, 28.2, 20.2; ¹⁹F NMR (471 MHz, CDCl₃) δ−167.97 (s, 1F).

Intermediate 5D. (±)-1-fluoro-6-oxabicyclo[3.2.1]octan-7-one

To a solution of intermediate 5C (350 mg, 1.30 mmol) and AIBN (21 mg,0.130 mmol) in benzene (5 mL) was added tris(trimethylsilyl)silane (0.60mL, 1.94 mmol) portionwise over 10 min at 60° C. The reaction wasstirred at 70° C. for 2 h, cooled to rt and then concentrated in vacuo.The residue was dissolved in EtOAc, washed with sat. aq. NH₄Cl, dried(MgSO₄) and concentrated in vacuo. The crude oil was chromatographed (12g SiO₂; continuous gradient from 0% to 30% EtOAc in Hexane over 10 min)to give the title compound (124 mg, 0.860 mmol, 66.4% yield) as a whitesolid. ¹⁹F NMR (471 MHz, CDCl₃) δ −167.01 (s, 1F); ¹H NMR (500 MHz,CDCl₃) δ 4.98-4.81 (m, 1H), 2.75 (dtdd, J=15.9, 6.8, 3.3, 1.7 Hz, 1H),2.24-1.89 (m, 5H), 1.82-1.65 (m, 1H), 1.60-1.46 (m, 1H); ¹³C NMR (126MHz, CDCl₃) δ 173.2, 173.0, 93.9, 92.3, 75.6, 75.5, 42.0, 41.9, 31.3,31.1, 26.7, 17.7, 17.6.

Intermediate 5

Acetyl chloride (0.061 mL, 0.860 mmol) was added portionwise to iPrOH (3mL) at 0° C. and then stirred at RT for 30 min Intermediate 5D (124 mg,0.860 mmol) was added and the reaction was stirred overnight at RT, thenwas concentrated in vacuo. The residual crude oil was chromatographed (4g SiO₂; continuous gradient from 0% to 50% EtOAc in Hexane over 10 min)to give the title compound (140 mg, 0.685 mmol, 80% yield) as a clearoil. ¹H NMR (500 MHz, CDCl₃) δ 5.08 (spt, J=6.3 Hz, 1H), 3.91 (tt,J=10.9, 4.4 Hz, 1H), 2.68 (br. s., 1H), 2.28 (dddt, J=13.5, 9.0, 4.6,2.1 Hz, 1H), 2.06-1.98 (m, 1H), 1.96-1.87 (m, 1H), 1.82-1.62 (m, 4H),1.37-1.22 (m, 7H); ¹⁹F NMR (471 MHz, CDCl₃) δ −162.93 (s, 1F); ¹³C NMR(126 MHz, CDCl₃) δ 170.9, 170.7, 95.7, 94.2, 69.3, 66.1, 40.7, 40.5,33.9, 31.6, 31.4, 21.5, 19.1.

Example 1.(1S,3S)-3-((6-(3-methyl-4-(((4-phenylpyrimidin-2-yl)amino)methyl)isoxazol-5-yl)pyridin-3-yl)oxy) cyclohexane-1-carboxylic Acid

1A. 4-(bromomethyl)-5-(5-bromopyridin-2-yl)-3-methylisoxazole

PBr₃ (0.21 mL, 2.23 mmol) was added to a solution of Intermediate 1A(200 mg, 0.743 mmol) in DME (10 mL) at 0° C. The reaction mixture wasallowed to warm to RT and stirred for 2 h at RT, then was cooled to 0°C. and neutralized to pH 7 with sat′d aq. NaHCO₃. The mixture waspartitioned between DCM (10 mL) and H₂O (10 mL), and the aqueous layerwas extracted with DCM (3×10 mL). The combined organic extracts weredried (MgSO₄) and concentrated in vacuo. The residue was chromatographed(24 g SiO₂, continuous gradient from 0 to 50% EtOAc:hexanes over 15 min)to provide the title compound (240 mg, 0.723 mmol, 97% yield) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ 8.82 (dd, J=2.5, 0.7 Hz, 1H), 7.99 (dd,J=8.5, 2.3 Hz, 1H), 7.83 (dd, J=8.4, 0.8 Hz, 1H), 4.97 (s, 2H), 2.44 (s,3H). [M+H]⁺=330.9.

1B.N-((5-(5-bromopyridin-2-yl)-3-methylisoxazol-4-yl)methyl)-4-phenylpyrimidin-2-amine

To a solution of 4-phenylpyrimidin-2-amine (116 mg, 0.678 mmol) in THF(2 mL) was added n-BuLi (0.42 mL of a 1.5 M solution in hexanes, 0.68mmol) at −78° C. The reaction mixture was allowed to warm slowly to RTand stirred for 5 min at RT. A solution of 1A (150 mg, 0.452 mmol) inTHF (1 mL) was quickly added, and the mixture was stirred at RT for 48h. The reaction mixture was diluted with H₂O (2 mL) and extracted withEtOAc (3×5 mL). The combined organic extracts were dried (MgSO₄) andconcentrated in vacuo. The residue was chromatographed (12 g SiO₂,continuous gradient from 0 to 50% EtOAc:hexanes over 12 min) to providethe title compound (172 mg, 0.407 mmol, 90% yield) as a slightly coloredsolid. ¹H NMR (500 MHz, CDCl₃) δ 8.86 (d, J=2.4 Hz, 1H), 8.35 (dd,J=11.3, 3.8 Hz, 1H), 7.99 (ddd, J=14.5, 8.0, 4.9 Hz, 3H), 7.83 (dd,J=20.3, 8.5 Hz, 1H), 7.48 (dd, J=5.0, 2.0 Hz, 3H), 6.98 (d, J=5.2 Hz,1H), 6.44 (t, J=6.8 Hz, 1H), 4.85 (d, J=6.6 Hz, 2H), 2.55 (s, 3H).[M+H]⁺=422.

1C.6-(3-methyl-4-(((4-phenylpyrimidin-2-yl)amino)methyl)isoxazol-5-yl)pyridin-3-ol

A mixture of Pd₂dba₃ (20 mg, 0.022 mmol),di-tert-butyl(2′,4′,6′-triisopropyl-11,1′-bi-phenyl]-2-yl)phosphine (37mg, 0.088 mmol), KOH (124 mg, 2.20 mmol), and 1B (155 mg, 0.367 mmol) in1,4-dioxane (2 mL) and H₂O (2 mL) was evacuated and backfilled with Ar(sequence repeated 3×). The mixture was stirred at 85° C. for 14 h, thenwas cooled to RT and acidified to pH 4 with aq. 1N HCl. EtOH (2 mL) wasadded, and the mixture was extracted with EtOAc (8×5 mL). The combinedorganic extracts were dried (MgSO₄) and concentrated in vacuo. Theresidual brown solid was chromatographed (12 g SiO₂, continuous gradientfrom 0 to 100% EtOAc:hexanes over 13 min) to provide the title compound(49 mg, 0.136 mmol, 37.1% yield) as a red solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.35 (d, J=2.9 Hz, 2H), 7.99 (s, 2H), 7.79 (d, J=8.6 Hz, 1H),7.49 (t, J=7.2 Hz, 1H), 7.43 (s, 2H), 7.37 (dd, J=8.6, 2.9 Hz, 1H), 7.18(d, J=5.2 Hz, 1H), 4.82 (s, 2H), 2.33 (s, 3H). [M+H]⁺=360.3.

1D. Isopropyl (1 S,3S)-3-((6-(3-methyl-4-(((4-phenylpyrimidin-2-yl)amino)methyl)isoxazol-5-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a mixture of 1C (17 mg, 0.047 mmol), (1S,3R)-isopropyl3-hydroxycyclohexane carboxylate (16 mg, 0.085 mmol), Et₃N (0.012 mL,0.085 mmol) and Ph₃P (23 mg, 0.085 mmol) in THF (0.5 mL) at 0° C. wasadded DIAD (0.017 mL, 0.085 mmol) dropwise over 2 min. The reaction wasstirred at RT for 18 h, then was concentrated in vacuo. The crudematerial was chromatographed (4 g SiO₂; continuous gradient from 0-100%EtOAc/hexanes over 20 min) to yield the title compound (20 mg, 0.037mmol, 79% yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 8.48 (d,J=2.9 Hz, 1H), 8.32 (d, J=5.1 Hz, 1H), 8.01 (d, J=4.6 Hz, 2H), 7.87 (dd,J=8.8, 4.7 Hz, 1H), 7.50-7.41 (m, 4H), 7.40-7.34 (m, 1H), 6.96 (d, J=5.2Hz, 1H), 4.82 (d, J=6.3 Hz, 2H), 4.79-4.72 (m, 1H), 2.83 (dtd, J=9.3,6.8, 4.2 Hz, 1H), 2.47 (s, 3H), 2.38-1.36 (m, 8H), 1.23 (d, J=6.3 Hz,6H). [M+H]⁺=528.3.

Example 1

A mixture of 1D (250 mg, 0.474 mmol) and LiOH.H₂O (398 mg, 9.48 mmol) inMeOH (2 mL), THF (5 mL) and H₂O (5 mL) was stirred at RT for 6 h, thenwas concentrated in vacuo. The residue was acidified with 1N aq. HCl topH=−3-4, then was extracted with EtOAc (5×5 mL). The combined organicextracts were dried (MgSO₄) and concentrated in vacuo. The crude productwas purified by preparative HPLC (YMC reverse phase ODS-A-5u 30×100 mmcolumn; flow rate=40 mL/min, 20 to 100% solvent B over 30 min, hold to40 min, where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to afford the title compound (135 mg, 0.272 mmol, 57.5%yield) as a white solid. LCMS [M+H]⁺=486.2. ¹H NMR (500 MHz, CDCl₃) δ8.62 (d, J=3.0 Hz, 1H), 8.21 (s, 1H), 8.04 (d, J=7.8 Hz, 2H), 7.89 (d,J=8.7 Hz, 1H), 7.69-7.62 (m, 1H), 7.56 (t, J=7.8 Hz, 2H), 7.38 (dd,J=8.7, 2.8 Hz, 1H), 7.18 (d, J=6.4 Hz, 1H), 5.08-4.93 (m, 2H), 4.81 (s,1H), 2.46 (s, 3H), 2.16-1.65 (m, 8H). hLPA1 IC₅₀=14 nM.

Example 2. (1 S,3S)-3-((6-(4-(((4-isopropyl-1,3,5-triazin-2-yl)amino)methyl)-3-methylisoxazol-5-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylicAcid

2A. isopropyl(1S,3S)-3-((6-(4-(((4-chloro-6-isopropyl-1,3,5-triazin-2-yl)amino)methyl)-3-methylisoxazol-5-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate

A solution of Intermediate 2 (10 mg, 0.026 mmol),2,4-dichloro-6-isopropyl-1,3,5-triazine (7 mg, 0.039 mmol) and iPr₂NEt(0.018 mL, 0.10 mmol) in THF (0.7 mL) was stirred at RT for 120 min, atwhich point LCMS analysis indicated the formation of the title compound.LCMS [M+H]⁺=543.2.

2B. Isopropyl(1S,3S)-3-((6-(4-(((4-isopropyl-1,3,5-triazin-2-yl)amino)methyl)-3-methyl-isoxazol-5-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate

To the above reaction mixture containing 2A was added 10% Pd/C (28 mg,0.026 mmol) and THF (3 mL). The reaction was stirred under 1 atmosphereof H₂ overnight, after which DCM (1 mL) was added. The mixture wasfiltered through a plug of Celite; the solids were washed with DCM (2mL), and the combined filtrates were concentrated in vacuo to afford thetitle compound. LCMS [M+H]⁺=509.08.

Example 2

To a solution of 2B (13 mg, 0.026 mmol) in THF (0.8 mL)/MeOH (0.4mL)/H₂O (0.4 mL) was added LiOH.H₂O (6 mg, 0.13 mmol). The mixture wasstirred at RT overnight, then was concentrated in vacuo. The residue wastaken up in EtOAc (2 mL)/H₂O (1 mL), and the solution was adjusted topH˜5 with 1N aq. HCl. The mixture was extracted with EtOAc (3×2 mL); thecombined organic extracts were dried (MgSO₄) and concentrated in vacuo.The residue was dissolved in DMF and purified via preparative LC/MS:Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95MeCN:H₂O with 0.1% TFA; Mobile Phase B: 95:5 MeCN:H₂O with 0.1% TFA;Gradient: 16-56% B over 20 min, then a 4-min hold at 100% B; Flow: 20mL/min Fractions containing the desired product were combined and driedvia centrifugal evaporation to afford the title compound (bis TFA salt;5.2 mg, 7.2 μmol, 28% yield; 96% purity by LCMS). LCMS [M+H]⁺=467.2. ¹HNMR (500 MHz, DMSO-d₆) δ 8.61-8.41 (m, 1H), 8.35 (br s, 1H), 7.78-7.70(m, 1H), 7.56 (br d, J=8.5 Hz, 1H), 4.91-4.74 (m, 3H), 2.82-2.61 (m,2H), 2.45 (m, 3H), 2.33 (m, 3H), 2.11-1.47 (m, 8H), 1.23-1.05 (m, 6H).hLPA1 IC₅₀=43 nM.

The Examples in Table 1 below were synthesized by the same proceduresdescribed above for preparing Examples 1 and 2.

TABLE 1 Ex # Structure & Name Analytical & Biological Data Method 3

LCMS, [M + H]⁺ = 486.1; ¹H NMR (500 MHz, DMSO- d₆) δ 8.53 (s, 1H), 8.37(d, J = 5.2 Hz, 1H), 7.98 (s, 2H), 7.89 (d, J = 8.9 Hz, 1H), 7.64 (d, J= 8.9 Hz, 1H), 7.51-7.35 (m, 4H), 7.18 (d, J = 5.1 Hz, 1H), 4.86 (br s,3H), 2.69 (br s, 1H), 2.34 (s, 3H), 2.05-1.48 (m, 8H); hLPA1 IC₅₀ = 18nM. Example 1 4

LCMS, [M + H]⁺ = 486.2; ¹H NMR (500 MHz, DMSO- d₆) δ 8.51 (s, 1H), 8.36(s, 1H), 7.98 (s, 2H), 7.87 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.7 Hz,1H), 7.56-7.32 (m, 4H), 7.18 (d, J = 5.2 Hz, 1H), 4.84 (br s, 2H), 4.57(s, 1H), 3.01 (s, 2H), 2.47-2.37 (m, 1H), 2.33 (m, 3H), 2.15-1.20 (m,8H); hLPA1 IC₅₀ = 39 nM. Example 1 5

LCMS, [M + H]⁺ = 485.0; ¹H NMR (500 MHz, DMSO- d₆) δ 8.52 (s, 1H), 8.10(s, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.59 (s,2H), 7.47 (s, 3H), 7.03 (br s, 2H), 4.87 (s, 1H), 4.82 (s, 2H),2.72-2.62 (m, 1H), 2.37 (s, 3H), 2.02-1.48 (m, 8H); hLPA1 IC₅₀ = 21 nM.Example 1 6

LCMS, [M + H]⁺ = 504.4; ¹H NMR (500 MHz, DMSO- d₆) δ 8.44 (s, 1H), 8.32(s, 1H), 7.91 (s, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 8.8 Hz,1H), 7.51-7.25 (m, 4H), 7.14 (d, J = 5.2 Hz, 1H), 4.93- 4.70 (m, 3H),2.31 (s, 3H), 2.13-1.09 (m, 8H); hLPA1 IC₅₀ = 7.8 nM. Example 1;Interme- diate 4 used instead of isopropyl trans-3- hydroxy cyclo-hexane- 1- carboxy- late 7

LCMS, [M + H]⁺ = 502.3. ¹H NMR (500 MHz, DMSO-d₆) δ 8.43 (s, 1H), 8.15(s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.61- 7.52 (m, 1H), 7.41 (t, J = 7.8Hz, 2H), 7.22 (t, J = 7.4 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 6.15-6.04(m, 1H), 4.82 (s, 1H), 4.55 (br s, 2H), 2.64 (br s, 1H), 2.24 (br s,3H), 2.13- 1.45 (m, 8H). hLPA1 IC₅₀ = 6.0 nM. Example 1 8

LCMS, [M + H]⁺ = 500.4; ¹H NMR (500 MHz, DMSO- d₆) δ 8.51 (s, 1H), 7.91(s, 2H), 7.86 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.36 (d, J= 71.9 Hz, 4H), 7.05 (s, 1H), 4.95-4.65 (m, 3H), 2.67- 2.58 (m, 1H),2.33 (br s, 3H), 2.26 (s, 3H), 2.00-1.46 (m, 8H); hLPA1 IC₅₀ = 16 nM.Example 1 9

LCMS, [M + H]⁺ = 516.1; ¹H NMR (500 MHz, DMSO- d₆) δ 8.43 (s, 1H), 7.82(d, J = 8.6 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.39 (t, J = 7.7 Hz, 2H),7.21 (t, J = 7.5 Hz, 1H), 7.12 (br s, 3H), 5.95 (s, 1H), 4.80 (s, 1H),4.56 (br s, 2H), 2.61-2.58 (m, 1H), 2.30 (br s, 3H), 2.11 (s, 3H),1.96-1.46 (m, 8H); hLPA1 IC₅₀ = 20 nM. Example 1 10

LCMS, [M + H]⁺ = 450.3; ¹H NMR (500 MHz, ¹H NMR (500 MHz, DMSO-d₆) δ8.47 (d, J = 2.9 Hz, 1H), 8.02 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.59(dd, J = 8.9, 2.8 Hz, 1H), 7.09 (s, 1H), 6.48 (d, J = 5.0 Hz, 1H), 4.84(m, 1H), 4.64 (d, J = 5.8 Hz, 2H), 2.69-2.61 (m, 1H), 2.28 (s, 3H),2.01- 1.45 (m, 9H), 0.77 (d, J = 47.4 Hz, 4H); hLPA1 IC₅₀ = 18 nM.Example 1 11

LCMS, [M + H]⁺ = 482.1; ¹H NMR (500 MHz, DMSO- d₆) δ 8.45 (s, 1H), 7.82(d, J = 8.7 Hz, 1H), 7.64 (d, J = 8.8, Hz, 1H), 5.79 (s, 1H), 4.78 (s,1H), 4.68 (s, 2H), 2.48-2.41 (m, 1H), 2.30 (s, 3H), 2.06 (m, 3H),2.03-1.39 (m, 8H), 1.03 (br s, 6H). (The methine proton on theisopropoxyl group is not observed due to water-suppression); hLPA1 IC₅₀= 17 nM. Example 1 12

LCMS, [M + H]⁺ = 507.4; ¹H NMR (500 MHz, DMSO- d₆) δ 8.48 (d, J = 2.8Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.60 (dd, J = 8.8, 2.9 Hz, 1H), 5.87(s, 1H), 4.83 (s, 1H), 4.63 (s, 2H), 2.67-2.58 (m, 1H), 2.31 (s, 3H),2.02 (s, 3H), 1.96- 1.24 (m, 14H). (The four piperidine —NCH₂ protonsare not observed due to water- suppression); hLPA1 IC₅₀ = 1100 nM.Example 1 13

LCMS, [M + H]⁺ = 487.3; ¹H NMR (500 MHz, Chloroform-d) δ 8.84 (d, J =4.7 Hz, 1H), 8.58 (d, J = 2.8 Hz, 1H), 8.39-8.31 (m, 2H), 7.97-7.86 (m,3H), 7.59 (dd, J = 7.6, 4.9 Hz, 1H), 7.41 (dd, J = 8.8, 2.8 Hz, 1H),5.08- 4.95 (m, 2H), 4.81 (s, 1H), 2.94 (tt, J = 8.8, 4.6 Hz, 1H), 2.49(s, 3H), 2.15-1.62 (m, 8H); hLPA1 IC₅₀ = 32 nM. Example 1 14

LCMS, [M + H]⁺ = 501.2; ¹H NMR (600 MHz, DMSO- d₆) δ 8.66 (d, J = 4.7Hz, 1H), 8.47-8.39 (m, 1H), 8.11 (br s, 1H), 7.72 (d, J = 8.6 Hz, 1H),7.54 (d, J = 8.7 Hz, 1H), 7.49 (d, J = 5.3 Hz, 2H), 5.01- 4.70 (m, 3H),2.67-2.59 (m, 1H), 2.46 (s, 3H), 2.32 (s, 3H), 2.07-1.43 (m, 8H); hLPA1IC₅₀ = 64 nM. Example 1 15

LCMS, [M + H]⁺ = 499.9; ¹H NMR (500 MHz, DMSO- d₆) δ 8.43 (d, J = 2.9Hz, 1H), 8.17 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.54 (d, J = 8.5 Hz,1H), 7.49-7.44 (m, 2H), 7.42- 7.32 (m, 2H), 7.09 (s, 1H), 4.79 (s, 1H),4.65 (d, J = 6.0 Hz, 2H), 2.66-2.57 (m, 1H), 2.27 (s, 3H), 2.08 (s, 3H),2.06- 1.44 (m, 8H); hLPA1 IC₅₀ = 4.9 nM. Example 1

Example 16. (1R,3S)-3-((6-(3-Methyl-4-(((4-phenylpyrimidin-2-amino)methyl)isoxazol-5-yl)pyridin-3-yl)oxy)cyclohexanecarboxylicAcid

To a 0° C. mixture of 4-phenylpyrimidin-2-amine (59 mg, 0.34 mmol) inDMF (1.5 mL) under N₂ was added NaH (14 mg of a 60% dispersion in oil,0.35 mmol). The reaction was stirred for 30 min at 0° C., after whichintermediate 1 (50 mg, 0.11 mmol) was added. The reaction was allowed towarm to RT and stirred at RT for 1 h. LCMS showed that the startingmaterial was completely consumed. The mixture was concentrated in acuoand the residue was purified by preparative LC/MS using the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 MeCN:H₂O with 10-mM aq. NH₄OAc; Mobile Phase B: 95:5 MeCN:H₂Owith 10-mM aq. NH₄OAc; Gradient: 20-65% B over 30 min, then a 5-min holdat 100% B; Flow: 20 mL/min. Fractions containing the desired productwere combined and dried via centrifugal evaporation. The title compound(7.8 mg, 13% yield) was obtained as a colorless oil. LCMS, [M+H]⁺=486.2.¹H NMR (500 MHz, DMSO-d₆) δ 8.51 (d, J=2.4 Hz, 1H), 8.40-8.30 (m, 1H),7.97 (br s, 2H), 7.87 (d, J=8.9 Hz, 1H), 7.64 (br dd, J=8.7, 2.6 Hz,1H), 7.52-7.34 (m, 4H), 7.17 (br d, J=5.2 Hz, 1H), 4.95-4.73 (br s, 2H),4.58 (m, 1H), 2.49-2.43 (m, 1H), 2.39-2.27 (m, 4H), 2.14-2.05 (m, 1H),1.94-1.79 (m, 2H), 1.52-1.21 (m, 4H). hLPA₁ IC₅₀=14 nM.

Example 17.(1S,3S)-3-((6-(4-(((4-Ethoxypyrimidin-2-yl)amino)methyl)-3-methylisoxazol-5-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylicAcid

To a solution of Intermediate 2 (10 mg, 0.03 mmol) in n-BuOH (0.4 mL)was added 2-chloro-4-ethoxypyrimidine (6.1 mg, 0.04 mmol) and iPr₂NEt(0.02 mL, 0.10 mmol) at RT. The mixture was stirred at 180° C. for 80min, then was cooled to RT. LiOH.H₂O (5.5 mg, 0.13 mmol) and THF (0.8mL)/MeOH (0.4 mL)/H₂O (0.4 mL) were added, and the reaction was stirredat RT overnight. The reaction mixture was concentrated in vacuo, dilutedwith H₂O (5 mL), and the pH adjusted with 1N aq. HCl to ˜5 and extractedwith EtOAc (3×5 mL). The combined organic extracts were washed withbrine (2 mL), dried (MgSO₄) and concentrated in vacuo. The crude productwas purified by preparative LC/MS using the following conditions:Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95MeCN:H₂O with 0.1% TFA; Mobile Phase B: 95:5 MeCN:H₂O with 0.1% TFA;Gradient: 15-55% B over 20 min, then a 4-min hold at 100% B; Flow: 20mL/min Fractions containing the desired product were combined and driedvia centrifugal evaporation. The title compound (14 mg, 96% yield) wasobtained as a colorless oil. LCMS, [M+H]⁺=468.2. ¹H NMR (500 MHz,DMSO-d₆) δ 8.05 (br d, J=5.8 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.53 (brd, J=8.8 Hz, 1H), 6.25 (br d, J=6.2 Hz, 1H), 4.88-4.75 (m, 3H), 4.25 (q,J=6.9 Hz, 2H), 2.68-2.58 (m, 1H), 2.45 (s, 3H), 2.31 (s, 3H), 2.06-1.45(m, 8H), 1.22 (br t, J=7.0 Hz, 3H). hLPA₁ IC₅₀=26 nM.

Analytical & Biological Ex # Structure & Name Data Method 18

LCMS, [M + H]⁺ = 499.3; ¹H NMR (500 MHz, DMSO-d₆) δ 8.88 (br s, 1H),7.93 (br d, J = 5.2 Hz, 1H), 7.74 (br d, J = 8.5 Hz, 1H), 7.56 (br d, J= 8.9 Hz, 1H), 4.91-4.76 (m, 3H), 2.65- 2.58 (m, 1H), 2.45 (s, 3H), 2.30(s, 3H), 2.08-1.41 (m, 8H), 1.01 (br s, 6H), (The α- CH of the iPr groupis not observed due to water- suppression); hLPA1 IC₅₀ = 88 nM. Example5 19

LCMS, [M + H]⁺ = 465.2; ¹H NMR (500 MHz, DMSO-d₆) δ 8.42-8.22 (m, 1H),7.94 (br s, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 8.7 H,z 1H),4.86-4.69 (m, 3H), 2.70-2.62 (m, 1H), 2.46 (s, 3H), 2.30 (s, 3H),2.08-2.00 (m, 1H), 1.93-1.48 (m, 8H), 1.01- 0.85 (m, 4H); hLPA1 IC₅₀ =76 nM. Example 2 20

LCMS, [M + H]⁺ = 479.1; ¹H NMR (500 MHz, DMSO-d₆) δ 8.58-8.33 (m, 1H),8.16 (br s, 1H), 7.71 (br d, J = 8.2 Hz, 1H), 7.52 (br d, J = 8.9 Hz,1H), 4.87-4.68 (m, 3H), 3.44-3.22 (m, 1H), 2.67-2.59 (m, 1H), 2.45-2.40(m, 3H), 2.33- 2.28 (m, 3H), 2.25-1.42 (m, 14H); hLPA₁ IC₅₀ = 64 nM.Example 2 21

LCMS, [M + H]⁺ = 493.3; ¹H NMR (500 MHz, DMSO-d₆) δ 8.58-8.29 (m, 2H),7.76-7.69 (m, 1H), 7.54 (br d, J = 8.5 Hz, 1H), 4.88-4.74 (m, 3H), 3.00-2.78 (m, 1H), 2.67-2.59 (m, 1H), 2.45-2.41 (m, 3H), 2.30 (s, 3H), 2.07-1.45 (m, 16H); hLPA1 IC₅₀ = 60 nM. Example 2 22

LCMS, [M + H]⁺ = 485.3; ¹H NMR (500 MHz, DMSO-d₆) δ 8.39 (br d, J = 4.6Hz, 1H), 8.09-7.95 (m, 2H), 7.73 (br d, J = 8.2 Hz, 2H), 7.65 (m, 1H),7.53- 7.41 (m, 3H), 7.20 (br d, J = 4.9 Hz, 1H), 7.11 (br d, J = 8.2 Hz,2H), 4.76-4.69 (m, 1H), 4.57 (br s, 2H), 2.64-2.58 (m, 1H), 2.31 (s,3H), 1.93-1.45 (m, 8H); hLPA1 IC₅₀ = 47 nM. Example 1 23

LCMS, [M + H]⁺ = 454.1; ¹H NMR (500 MHz, DMSO-d₆) δ 8.47 (d, J = 2.2 Hz,1H), 7.99 (br d, J = 5.5 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.59 (dd, J= 8.7, 2.4 Hz, 1H), 6.01 (d, J = 5.7 Hz, 1H), 4.83 (br s, 1H), 4.71 (brs, 2H), 4.18-4.08 (m, 2H), 2.73-2.64 (m, 1H), 2.31 (s, 3H), 2.02-1.50(m, 8H), 1.19 (br t, J = 6.9 Hz, 3H); hLPA1 IC₅₀ = 14 nM. Example 5 24

LCMS, [M + H]⁺ = 485.1; ¹H NMR (500 MHz, DMSO-d₆) δ 8.46 (d, J = 2.4 Hz,1H), 7.94-7.84 (m, 2H), 7.63 (dd, J = 8.7, 2.7 Hz, 1H), 4.88-4.73 (m,3H), 4.16-4.03 (m, 1H), 2.73- 2.63 (m, 1H), 2.32 (s, 3H), 2.03-1.50 (m,8H), 1.08 (d, J = 6.6 Hz, 6H); hLPA1 IC₅₀ = 32 nM. Example 5 25

LCMS, [M + H]⁺ = 451.1; ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.75 (s, 0.5H),8.58 (s, 0.5H), 8.47-8.43 (m, 1H), 7.95- 7.90 (m, 1H), 7.44-7.38 (m,1H), 4.86-4.68 (m, 3H), 2.98-2.87 (m, 1H), 2.46-2.40 (m, 3H), 2.36- 2.19(m, 1H), 2.15-1.59 (m, 8H), 1.47-1.30 (m, 4H); hLPA1 IC₅₀ = 29 nM.Example 2 26

LCMS, [M + H]⁺ = 453.2; ¹H NMR (500 MHz, DMSO-d₆) δ 8.54-8.35 (m, 2H),8.17-7.99 (m, 1H), 7.85 (br d, J = 8.5 Hz, 1H), 7.61 (br d, J = 7.9 Hz,1H), 4.89-4.68 (m, 3H), 2.77- 2.57 (m, 2H), 2.31 (br s, 3H), 2.01-1.48(m, 8H), 1.20-1.02 (m, 6H); hLPA1 IC₅₀ = 38 nM. Example 2 27

LCMS, [M + H]⁺ = 465.1; ¹H NMR (500 MHz, DMSO-d₆) δ 8.56-8.36 (m, 2H),8.03-7.80 (m, 2H), 7.59 (br d, J = 6.6 Hz, 1H), 4.87-4.69 (m, 3H), 3.55-3.39 (m, 1H), 2.74-2.63 (m, 1H), 2.32 (s, 3H), 2.23- 1.50 (m, 14H);hLPA1 IC₅₀ = 33 nM. Example 2 28

LCMS, [M + H]⁺ = 479.1; ¹H NMR (500 MHz, DMSO-d₆) δ 85.1-8.33 (m, 2H),8.18-7.96 (m, 1H), 7.87-7.81 (m, 1H), 7.64- 7.58 (m, 1H), 4.86-4.68 (m,3H), 2.95-2.68 (m, 1H), 2.67-2.60 (m, 1H), 2.30 (s, 3H), 1.98-1.45 (m,16H); hLPA₁ IC₅₀ = 24 nM. Example 2

Example 29.(±)-Cis-3-(4-(3-Methyl-4-(((4-phenylpyrimidin-2-yl)oxy)methyl)isoxazol-5-yl)phenoxy)cyclo-hexanecarboxylic Acid

Example 30.(±)-Trans-3-(4-(3-methyl-4-(((4-phenylpyrimidin-2-yl)oxy)methyl)isoxazol-5-yl) phenoxy)cyclohexanecarboxylic Acid

To a solution of Intermediate 3 (15 mg, 0.04 mmol) in THF (0.3 mL) wasadded NaOtBu (4.6 mg, 0.05 mmol). The reaction mixture was stirred at RTfor 1 h; 2-chloro-4-phenyl-pyrimidine (7.7 mg, 0.04 mmol) was then addedand the reaction was stirred at 50° C. for 1 h, then was cooled to RT.LCMS indicated the formation of the desired oxy-pyrimidine product. THF(0.8 mL), H₂O (0.4 mL) and LiOH.H₂O (13.4 mg, 0.32 mmol) were added atRT. The reaction was stirred at RT overnight, then was concentrated invacuo; the residue was diluted with H₂O (5 mL) and the pH was adjustedwith 1N aq. HCl to ˜3 and extracted with EtOAc (3×5 mL). The combinedorganic extracts were washed with brine (2 mL), dried (MgSO₄) andconcentrated in vacuo. The crude product was purified via preparativeLC/MS using the following conditions: Column: XBridge C18, 19×200 mm,5-μm particles; Mobile Phase A: 5:95 MeCN:H₂O with 10-mM aq. NH₄OAc;Mobile Phase B: 95:5 MeCN:H₂O with 10-mM aq. NH₄OAc; Gradient: 25-65% Bover 25 min, then a 5-min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation.

Example 29 (first eluting isomer; 4.4 mg, 23% yield): LCMS,[M+H]⁺=486.0. ¹H NMR (500 MHz, DMSO-d₆) δ 8.70 (br d, J=4.9 Hz, 1H),8.14 (br d, J=7.3 Hz, 2H), 7.80-7.70 (m, 3H), 7.46 (s, 3H), 7.15 (br d,J=8.2 Hz, 2H), 5.50 (s, 2H), 4.54-4.39 (m, 1H), 2.45 (m, 1H), 2.38 (s,3H), 2.33-2.23 (m, 1H), 2.12-2.02 (m, 1H), 1.96-1.78 (m, 2H), 1.51-1.20(m, 4H). hLPA₁ IC₅₀=209 nM.

Example 30 (second eluting isomer; 3.2 mg, 17% yield): LCMS,[M+H]⁺=486.0. ¹H NMR (500 MHz, DMSO-d₆) δ 8.70 (br d, J=4.9 Hz, 1H),8.14 (br d, J=7.3 Hz, 2H), 7.81-7.71 (m, 3H), 7.61-7.48 (m, 3H), 7.15(br d, J=8.2 Hz, 2H), 5.50 (s, 2H), 4.80-4.69 (m, 1H), 2.72-2.61 (m,1H), 2.38 (s, 3H), 2.01-1.47 (m, 8H). hLPA₁ IC₅₀=47 nM.

Other features of the invention should become apparent in the course ofthe above descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof. The present invention may be embodied in other specific formswithout departing from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsounderstood that each individual element of the embodiments is its ownindependent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

What is claimed is:
 1. A compound according to Formula (Ia) or Formula(Ib):

or a stereoisomer, tautomer, or pharmaceutically acceptable salt orsolvate thereof, wherein X¹, X², X³, and X⁴ are each independently CR⁶or N; provided that no more than two of X¹, X², X³, or X⁴ are N; L is acovalent bond or C₁₋₄ alkylene substituted with 0 to 4 R⁷; Z is NR⁸ orO; the Y ring is phenyl or an azine moiety; R¹ is (—CH₂)_(a)R⁹; a is aninteger of 0 or 1; R² is each independently halo, cyano, hydroxyl,amino, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₄₋₆ heterocyclyl, alkylamino,haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl,haloalkoxyalkyl, or haloalkoxy; n is an integer of 0, 1, or 2; R³ ishalo, cyano, hydroxyl, amino, oxo, —OR^(a), —SR^(a), ═S, —NR^(c)R^(c),═NH, ═N—OH, ═NR^(a), ═N—OR^(a), —NO₂, —S(O)₂R^(a), —S(O)₂NHR^(b),—S(O)₂NR^(c)R^(c), —S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂OR^(b),—P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(NR^(b))R^(b), —C(O)OR^(b),—C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —NR^(b)C(O)R^(b),—OC(O)OR^(b), —NR^(b)C(O)OR^(b), —OC(O)NR^(c)R^(c),—NR^(b)C(O)NR^(c)R^(c), —NR^(b)(NR^(b))R^(b),—NR^(b)C(NR^(b))NR^(c)R^(c), C₁₋₆ alkyl, C₁₋₆ deuterated alkyl, C₁₋₆heteroalkyl, 6- to 10-membered aryl, arylalkyl, 5- to 10-memberedheteroaryl, heteroarylalkyl, 3- to 8-membered carbocyclyl,carbocyclylalkyl, 4- to 8-membered heterocyclyl, or heterocyclylalkyl;wherein the alkyl, heteroalkyl, aryl, heteroaryl, carbocyclyl,heterocyclyl, and R^(a), by themselves or as part of another group, areeach independently substituted with 0 to 5 R^(d), R^(a) is selected fromC₁₋₆ alkyl, C₁₋₆ deuterated alkyl, haloalkyl, hydroxyalkyl, aminoalkyl,alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, andheterocyclylalkyl; R^(b) is each independently hydrogen or R^(a); R^(c)is each independently R^(b); or alternatively, two R^(c), taken togetherwith the nitrogen atom to which they are attached, form a 4- to7-membered heterocyclyl; R^(d) is each independently selected fromR^(a), alkoxy, haloalkoxy, alkylamino, cycloalkylamino,heterocyclylamino, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkoxy,heterocyclyloxy, haloalkoxy, alkoxyalkoxy, haloalkylamino,alkoxyalkylamino, haloalkoxyalkylamino, arylamino, aralkylamino,aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, alkylthio, halo,cyano, hydroxyl, amino, oxo, —OR^(a), —SR^(a), ═S, —NR^(c)R^(c), ═NH,═N—OH, ═NR^(a), ═N—OR^(a), —NO₂, —S(O)₂R^(a), —S(O)₂NHR^(b),—S(O)₂NR^(c)R^(c), —S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂OR^(b),—P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(NR^(b))R^(b), —C(O)OR^(b),—C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —NR^(b)C(O)R^(b),—OC(O)OR^(b), —NR^(b)C(O)OR^(b), —NR^(b)C(O)NR^(c)R^(c),—NR^(b)C(NR^(b))R^(b), and —NR^(b)C(NR^(b))NR^(c)R^(c); or alternativelyone or two R^(d) on alkyl, heteroalkyl, aryl, heteroaryl, carbocyclyl,or heterocyclyl, taken together with the atoms to which the R^(d) isattached, form a cyclic or bridge moiety; R⁴ is each independently halo,cyano, hydroxyl, amino, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₄₋₆ heterocyclyl,alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl,haloalkoxyalkyl, or haloalkoxy; or R³ and R⁴, taken together with theatoms to which they are attached, form a monocyclic or bicyclic ringmoiety; m is an integer of 0, 1, or 2; R⁵ and R⁶ are each independentlyhydrogen, halo, cyano, hydroxyl, amino, C₁₋₆ alkyl, alkylamino,haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl,alkoxy, or haloalkoxy; R⁷ is halo, oxo, cyano, hydroxyl, amino, C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₄₋₆ heterocyclyl, alkylamino, haloalkyl,hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, orhaloalkoxy; R⁸ is hydrogen or C₁₋₄ alkyl; R⁹ is selected from —CN,—C(O)OR¹⁰, —C(O)NR^(11a)R^(11b),

R^(e) is C₁₋₆ alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,or haloalkoxyalkyl; R¹⁰ is hydrogen or C₁₋₁₀ alkyl; and R^(11a) andR^(11b) are each independently hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₄₋₆ heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl,alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy.
 2. The compoundaccording to claim 1, wherein the

moiety is

and Y¹, Y², Y³, and Y⁴ are each independently N or CH with the provisothat at least one of Y¹, Y², Y³, and Y⁴ is CH.
 3. The compound accordingto claim 2, wherein R³ is halo, cyano, hydroxyl, amino, —OR^(a),—SR^(a),—NR^(c)R^(c), C₁₋₆ alkyl, C₁₋₆ heteroalkyl, 6- to 10-membered aryl,arylalkyl, 5- to 10-membered heteroaryl, heteroarylalkyl, 3- to8-membered carbocyclyl, carbocyclylalkyl, 4- to 8-membered heterocyclyl,or heterocyclylalkyl; wherein the alkyl, heteroalkyl, aryl, heteroaryl,carbocyclyl, heterocyclyl, and R^(a), by themselves or as part ofanother group, are each independently substituted with 0 to 5 R^(d),R^(a) is selected from C₁₋₆ alkyl, haloalkyl, hydroxyalkyl, aminoalkyl,alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, andheterocyclylalkyl; R^(b) is each independently hydrogen or R^(a); R^(c)is each independently R^(b); or alternatively, two R^(c), taken togetherwith the nitrogen atom to which they are attached, form a 4- to7-membered heterocyclyl; R^(d) is each independently selected fromR^(a), alkoxy, haloalkoxy, alkylamino, cycloalkylamino,heterocyclylamino, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkoxy,heterocyclyloxy, haloalkoxy, alkoxyalkoxy, haloalkylamino,alkoxyalkylamino, haloalkoxyalkylamino, arylamino, aralkylamino,aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, alkylthio, halo,cyano, hydroxyl, amino, oxo, —OR^(a), —SR^(a), and —NR^(c)R^(c); oralternatively one or two R^(d) on alkyl, heteroalkyl, aryl, heteroaryl,carbocyclyl, or heterocyclyl, taken together with the atoms to which theR^(d) is attached, form a cyclic or bridge moiety.
 4. The compoundaccording to claim 3, which is represented by Formula (IIa) or Formula(IIb):

Y¹, Y², Y³, and Y⁴ are each independently N or CH; R^(7a) is hydrogen,halo, oxo, cyano, hydroxyl, amino, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₄₋₆heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl,alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; f is an integer of0, 1, or 2; n is 0 or 1; and R⁵ is hydrogen or C₁₋₄ alkyl.
 5. Thecompound according to claim 4, wherein X¹ is CR⁶, where R⁶ is hydrogenor C₁₋₄ alkyl.
 6. The compound according to claim 5, wherein X³ is N. 7.The compound according to claim 6, wherein the

moiety is selected from

R^(6a) is each independently halo, cyano, hydroxyl, amino, C₁₋₆ alkyl,alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,haloalkoxyalkyl, alkoxy, or haloalkoxy; and d is an integer of 0, 1, or2.
 8. The compound according to claim 7, wherein f is 0 or
 1. 9. Thecompound according to claim 8, wherein R⁸ is hydrogen or methyl.
 10. Thecompound according to claim 9, wherein R¹ is CO₂H.
 11. The compoundaccording to claim 1, which is represented by Formula (IIIa) or (IIIb):

Y¹, Y², and Y³ are each independently N or CH; R^(2a) is hydrogen,chloro, fluoro, or C₁₋₄ alkyl; L is a covalent bond or CH₂; and Z is Oor NH.
 12. The compound according to claim 11, wherein the

moiety is selected from


13. The compound according to claim 12, wherein R¹ is CO₂H.
 14. Thecompound according to claim 13, wherein X¹ is CR⁶; X² is N or CH; X³ isN; and X⁴ is N or CH; and R⁶ is hydrogen, halo, cyano, C₁₋₆ alkyl,haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, or alkoxy.
 15. Thecompound according to claim 14, wherein the

moiety is selected from


16. The compound according to claim 15, wherein the

moiety is

m is 0 or
 1. 17. The compound according to claim 16, wherein R⁴ is C₁₋₄alkyl, C₁₋₄ alkoxy, or halo.
 18. The compound according to claim 17,wherein R³ is halo, cyano, hydroxyl, amino, —OR^(a), —SR^(a),—NR^(c)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ heteroalkyl, 6- to10-membered aryl, arylalkyl, 5- to 10-membered heteroaryl,heteroarylalkyl, 3- to 8-membered carbocyclyl, carbocyclylalkyl, 4- to8-membered heterocyclyl, or heterocyclylalkyl; wherein the alkyl,heteroalkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, and R^(a), bythemselves or as part of another group, are each independentlysubstituted with 0 to 5 R^(d), R^(a) is selected from C₁₋₆ alkyl,haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, carbocyclylalkyl,heterocyclyl, and heterocyclylalkyl; R^(b) is each independentlyhydrogen or R^(a); R^(c) is each independently R^(b); or alternatively,two R^(c), taken together with the nitrogen atom to which they areattached, form a 4- to 7-membered heterocyclyl; R^(d) is eachindependently selected from R^(a), alkoxy, haloalkoxy, alkylamino,cycloalkylamino, heterocyclylamino, haloalkyl, hydroxyalkyl, aminoalkyl,cycloalkoxy, heterocyclyloxy, haloalkoxy, alkoxyalkoxy, haloalkylamino,alkoxyalkylamino, haloalkoxyalkylamino, arylamino, aralkylamino,aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, alkylthio, halo,cyano, hydroxyl, amino, oxo, —OR^(a), —SR^(a), and —NR^(c)R^(c); oralternatively one or two R^(d) on alkyl, heteroalkyl, aryl, heteroaryl,carbocyclyl, or heterocyclyl, taken together with the atoms to which theR^(d) is attached, form a cyclic or bridge moiety. m is 0, 1, or 2; andR⁴ is each independently halo, cyano, hydroxyl, amino, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₄₋₆ heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl,aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl, or haloalkoxy.
 19. Thecompound according to claim 18, wherein R³ is C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, phenyl,benzyl, (a 6-membered heteroaryl containing 1 to 3 heteroatoms each ofwhich is independently selected from N, O, and S), alkoxy,—O-cycloalkyl, —O-phenyl, —O-benzyl, and —NH-alkyl; and each of thealkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, phenyl, benzyl, andheteroaryl, by itself or as part of another group, is independentlysubstituted with 0 to 3 R^(d); and R^(d) is halo, cyano, hydroxyl,amino, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, or alkoxy.
 20. A pharmaceuticalcomposition comprising one or more compounds according to claim 1, or astereoisomer, tautomer, or pharmaceutically acceptable salt or solvatethereof; and a pharmaceutically acceptable carrier or diluent.
 21. Amethod of relieving the disease-state and/or reducing the risk of adisease, disorder, or condition selected from idiopathic pulmonaryfibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholicfatty liver disease (NAFLD), chronic kidney disease, diabetic kidneydisease, and systemic sclerosis, in a patient having the disease,disorder, or condition, comprising administering a therapeuticallyeffective amount of a compound or a stereoisomer, a tautomer, or apharmaceutically acceptable salt or solvate thereof according toclaim
 1. 22. A pharmaceutical composition comprising one or morecompounds according to claim 11, or a stereoisomer, tautomer, orpharmaceutically acceptable salt or solvate thereof; and apharmaceutically acceptable carrier or diluent.
 23. A pharmaceuticalcomposition comprising one or more compounds according to claim 12, or astereoisomer, tautomer, or pharmaceutically acceptable salt or solvatethereof; and a pharmaceutically acceptable carrier or diluent.
 24. Apharmaceutical composition comprising one or more compounds according toclaim 13, or a stereoisomer, tautomer, or pharmaceutically acceptablesalt or solvate thereof; and a pharmaceutically acceptable carrier ordiluent.
 25. A pharmaceutical composition comprising one or morecompounds according to claim 14, or a stereoisomer, tautomer, orpharmaceutically acceptable salt or solvate thereof; and apharmaceutically acceptable carrier or diluent.
 26. A pharmaceuticalcomposition comprising one or more compounds according to claim 15, or astereoisomer, tautomer, or pharmaceutically acceptable salt or solvatethereof; and a pharmaceutically acceptable carrier or diluent.
 27. Apharmaceutical composition comprising one or more compounds according toclaim 16, or a stereoisomer, tautomer, or pharmaceutically acceptablesalt or solvate thereof; and a pharmaceutically acceptable carrier ordiluent.
 28. A pharmaceutical composition comprising one or morecompounds according to claim 17, or a stereoisomer, tautomer, orpharmaceutically acceptable salt or solvate thereof; and apharmaceutically acceptable carrier or diluent.
 29. A pharmaceuticalcomposition comprising one or more compounds according to claim 18, or astereoisomer, tautomer, or pharmaceutically acceptable salt or solvatethereof; and a pharmaceutically acceptable carrier or diluent.
 30. Apharmaceutical composition comprising one or more compounds according toclaim 19, or a stereoisomer, tautomer, or pharmaceutically acceptablesalt or solvate thereof; and a pharmaceutically acceptable carrier ordiluent.